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CN102786570B - Macrolides compound, its preparation method, application and intermediate - Google Patents

Macrolides compound, its preparation method, application and intermediate Download PDF

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CN102786570B
CN102786570B CN201110129340.0A CN201110129340A CN102786570B CN 102786570 B CN102786570 B CN 102786570B CN 201110129340 A CN201110129340 A CN 201110129340A CN 102786570 B CN102786570 B CN 102786570B
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clarithromycin
dichloromethane
water
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CN102786570A (en
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沈舜义
袁芳
葛涵
张志宏
刘毓彬
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Shanghai Institute of Pharmaceutical Industry
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

本发明公开了一类如式I所示的大环内酯类化合物、其制备方法、应用以及中间体。本发明的大环内酯类化合物对大部分受试G+菌都有很强的活性,其中两类化合物对部分革兰氏阳性菌的活性比阿奇霉素更高。 The invention discloses a class of macrolide compound represented by formula I, its preparation method, application and intermediate. The macrocyclic lactone compounds of the present invention have strong activity against most tested G + bacteria, and the activity of two types of compounds is higher than that of azithromycin against some Gram-positive bacteria.

Description

大环内酯类化合物、其制备方法、应用以及中间体Macrolide compound, its preparation method, application and intermediate

技术领域 technical field

本发明具体的涉及一种大环内酯类化合物、其制备方法、应用以及中间体。The present invention specifically relates to a macrocyclic lactone compound, its preparation method, application and intermediate.

背景技术 Background technique

大环内酯类抗生素应用于临床各科的抗感染已经有50多年的历史,具有安全性高、价格低廉、口服吸收好等优点,在感染性疾病的治疗中发挥着重要作用。Macrolide antibiotics have been used in clinical anti-infection for more than 50 years. They have the advantages of high safety, low price, and good oral absorption. They play an important role in the treatment of infectious diseases.

对大环内酯类抗生素化学结构修饰工作以药物作用机制研究为基础,经历了三个发展阶段。早期主要将其改造成酯类、盐类以改善苦味,增强稳定性,提高生物利用度。20世纪70年代,红霉素A酸性失活机理被阐明,此后对红霉素A的改造主要针对参与酸降解的活性位点,得到了以克拉霉素、阿奇霉素为代表的第二代大环内酯类化合物,对酸稳定性提高,药物动力学性质改善。随着世界范围内耐药菌问题的日益严重,第二代大环内酯类抗生素显示出其对耐药菌活性差的弱点。到90年代,研究发现克拉定糖是诱导细菌产生耐药性的主要基团,针对该部位进行改造,得到了酮内酯、4″-氨基甲酸酯、酰内酯、2,3-脱水烯内酯等第三代大环内酯类抗生素,克服了细菌的诱导耐药性,对耐药菌活性强。The work on the chemical structure modification of macrolide antibiotics is based on the research on the mechanism of drug action, and has gone through three development stages. In the early days, it was mainly transformed into esters and salts to improve bitterness, enhance stability, and increase bioavailability. In the 1970s, the acidic inactivation mechanism of erythromycin A was elucidated. Since then, the modification of erythromycin A mainly targeted at the active site involved in acid degradation, and the second-generation macrocycles represented by clarithromycin and azithromycin were obtained. Lactone compounds have improved acid stability and improved pharmacokinetic properties. With the increasingly serious problem of drug-resistant bacteria worldwide, the second-generation macrolide antibiotics show their weakness of poor activity against drug-resistant bacteria. In the 1990s, it was found that cladinose was the main group that induces bacterial drug resistance, and this part was modified to obtain ketolide, 4″-carbamate, acyl lactone, 2,3-dehydration The third-generation macrolide antibiotics such as enolactones overcome the induced drug resistance of bacteria and have strong activity against drug-resistant bacteria.

展望大环内酯类抗生素的发展,寻找对耐药菌有效的大环内酯类抗生素仍是研究的热点和重点。Looking forward to the development of macrolide antibiotics, finding effective macrolide antibiotics against drug-resistant bacteria is still a research focus and focus.

发明内容 Contents of the invention

本发明所要解决的技术问题是提供了一类与现有技术完全不同的大环内酯类化合物、其制备方法、应用以及中间体。本发明的大环内酯类化合物对大部分受试G+菌都有很强的活性,其中两类化合物对部分革兰氏阳性菌的活性比阿奇霉素更高。The technical problem to be solved by the present invention is to provide a class of macrolide compounds completely different from the prior art, its preparation method, application and intermediate. The macrocyclic lactone compounds of the present invention have strong activity against most tested G + bacteria, and the activity of two types of compounds is higher than that of azithromycin against some Gram-positive bacteria.

因此,本发明涉及一类如式I所示的大环内酯类化合物;Therefore, the present invention relates to a class of macrolide compounds as shown in formula I;

其中,R为C1~C3烷基,或H;Ra 3位的表示单键或双键,其为双键时,Rb不存在,其为单键时,Rb Wherein, R is C 1 ~C 3 alkyl, or H; R a is 3 digits Represents a single bond or a double bond. When it is a double bond, R b does not exist. When it is a single bond, R b is

Rc为取代或未取代的C1~C3烷基(优选甲基、乙基或异丙基)、取代或未取代的C6~C10芳基、或者取代或未取代的C2~C4烯基(优选乙烯基);其中,取代的C6~C10芳基中的取代基为硝基或卤素(卤素优选C1),芳基中的取代基可为邻位、对位或间位;取代的C1~C3烷基中的取代基为C6~C10芳基,或者C4~C8杂芳基(优选2-噻吩基或3-吲哚基),其中杂原子为N、O或S;取代的C2~C4烯基中的取代基为C6~C10芳基;R c is substituted or unsubstituted C 1 -C 3 alkyl (preferably methyl, ethyl or isopropyl), substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted C 2 - C 4 alkenyl (preferably vinyl); wherein, the substituent in the substituted C 6 ~C 10 aryl is nitro or halogen (halogen is preferably C1), and the substituent in the aryl can be ortho, para or meta-position; the substituent in the substituted C 1 -C 3 alkyl is C 6 -C 10 aryl, or C 4 -C 8 heteroaryl (preferably 2-thienyl or 3-indolyl), wherein hetero The atom is N, O or S; the substituent in the substituted C 2 -C 4 alkenyl is C 6 -C 10 aryl;

X1和X2独立的为卤素,如氟、氯、溴或碘,X1和X2的位置可为2’位和5’位;较佳的,X1和X2相同;X1 and X2 are independently halogen, such as fluorine, chlorine, bromine or iodine, and the positions of X1 and X2 can be 2 ' and 5 '; preferably, X1 and X2 are the same ;

Rd和Re独立的为C1~C3烷基(优选乙基);R d and R e are independently C 1 -C 3 alkyl (preferably ethyl);

n为1~3(优选2)。n is 1-3 (preferably 2).

本发明中,所述的化合物I较佳的为如下任一结构:In the present invention, the compound I is preferably any of the following structures:

其中,Ra和Rc的定义均同前所述。Wherein, the definitions of Ra and Rc are the same as those mentioned above.

本发明中,所述的化合物I更佳的为如下任一化合物:In the present invention, the compound I is more preferably any of the following compounds:

Ia中,Rc为甲基、苯基、对硝基苯基、对氯苯基、苄基、苯乙基、苯乙烯基、噻吩-2-甲基、吲哚-3-甲基或吲哚-3-丙基;In Ia, R c is methyl, phenyl, p-nitrophenyl, p-chlorophenyl, benzyl, phenethyl, styryl, thiophene-2-methyl, indole-3-methyl or indole Indole-3-propyl;

Ib中,Rc为苯基、对硝基苯基、对氯苯基、苄基、苯乙基、苯乙烯基或异丙基;In Ib, R c is phenyl, p-nitrophenyl, p-chlorophenyl, benzyl, phenethyl, styryl or isopropyl;

Ic中,Ra In Ic, R a is

对于本发明的化合物I的制备,本领域技术人员均可参考本领域现有技术进行,即可制得相应的目标产物。For the preparation of compound I of the present invention, those skilled in the art can refer to the prior art in the art to obtain the corresponding target product.

本发明进一步涉及上述化合物I的制备方法,其为下述方法中的任意一种:The present invention further relates to a preparation method of the above-mentioned compound I, which is any one of the following methods:

(一)当目标化合物I中,RaR为C1~C3烷基时,将化合物II进行脱去羟基的酰基保护基的反应,即可;(1) When the target compound I, R a is When R is a C 1 -C 3 alkyl group, the compound II is subjected to the reaction of removing the acyl protecting group of the hydroxyl group;

Rc1为Rc或者本领域常规的酰基保护基上的取代基;R c1 is a substituent on R c or a conventional acyl protecting group in the art;

(二)当目标化合物I中,RaR为H或C1~C3烷基时,将化合物II’和RaX进行如下所示的亲核取代反应,即可;(2) When the target compound I, R a is When R is H or C 1 -C 3 alkyl, compound II' and R a X are subjected to the following nucleophilic substitution reaction;

其中,X为本领域此类亲核取代反应中常规的离去基团,如卤素(优选氯、溴或碘)。Wherein, X is a conventional leaving group in this type of nucleophilic substitution reaction in the art, such as halogen (preferably chlorine, bromine or iodine).

上述两种方法中,涉及的反应的方法和条件均可为本领域相应类别的反应中的常规方法和条件;各基团的定义除特别说明外均同前所述。In the above two methods, the methods and conditions of the reactions involved can be conventional methods and conditions in the corresponding category of reactions in the art; the definitions of each group are the same as those mentioned above unless otherwise specified.

本发明中的化合物I可根据现有技术,采用任意适宜的有机合成方法制备。下面将本发明中,化合物I的优选的制备方法举例说明:Compound I in the present invention can be prepared by any suitable organic synthesis method according to the prior art. In the present invention, the preferred preparation method of compound I is illustrated below:

(一)化合物Ia系列的制备,反应路线如下:(1) The preparation of compound Ia series, reaction scheme is as follows:

以克拉霉素为起始原料,与乙酸肼反应生成9-腙克拉霉素,再双酰化,脱2’位酰化保护得目标化合物。Using clarithromycin as the starting material, react with hydrazine acetate to generate 9-hydrazone clarithromycin, then diacylate and de-acylate the 2' position to obtain the target compound.

其中各基团定义同前所述。本领域技术人员参照上述反应路线,按照现有技术和常规知识,即可制得化合物Ia。Wherein the definition of each group is as described above. Those skilled in the art can prepare compound Ia by referring to the above reaction scheme and according to the prior art and common knowledge.

(二)化合物Ib系列的制备,反应路线如下:(2) The preparation of compound Ib series, reaction scheme is as follows:

以克拉霉素为起始原料,与乙酸肼反应生成9-腙克拉霉素,再双酰化,脱克拉定糖,氧化,脱酰化,得目标化合物。Using clarithromycin as the starting material, it reacts with hydrazine acetate to generate 9-hydrazone clarithromycin, then diacylates, removes claridinose, oxidizes, and deacylates to obtain the target compound.

其中各基团定义同前所述。本领域技术人员参照上述反应路线,按照现有技术和常规知识,即可制得化合物Ib。Wherein the definition of each group is as described above. Those skilled in the art can prepare compound Ib according to the prior art and conventional knowledge by referring to the above reaction scheme.

(三)化合物Ic系列的制备,合成路线如下:(3) Preparation of compound Ic series, the synthetic route is as follows:

以硫氰酸红霉素A为原料,经成腙、脱硫氰酸根、烷基化三步反应得目标化合物。Using erythromycin A thiocyanate as raw material, the target compound can be obtained through three steps of hydrazone formation, dethiocyanate radical and alkylation.

其中各基团定义同前所述。本领域技术人员参照上述反应路线,按照现有技术和常规知识,即可制得化合物Ic。Wherein the definition of each group is as described above. Those skilled in the art can prepare compound Ic by referring to the above reaction scheme and according to the prior art and common knowledge.

因此,本发明进一步涉及制备上述化合物I的中间体化合物IIa、IIb或IIIb:Accordingly, the present invention further relates to intermediate compounds IIa, IIb or IIIb for the preparation of compound I above:

其中,各基团的定义均同前所述。Wherein, the definition of each group is the same as above.

本发明还涉及上述化合物I在制备抗生素药物中的应用。The present invention also relates to the application of the above compound I in the preparation of antibiotic drugs.

在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.

本发明的积极进步效果在于:本发明的大环内酯类化合物对大部分受试G+菌都有很强的活性,其中两类化合物对部分革兰氏阳性菌的活性比阿奇霉素更高。The positive and progressive effect of the present invention is that the macrolide compounds of the present invention have strong activity against most tested G + bacteria, and two types of compounds have higher activity than azithromycin against some Gram-positive bacteria.

具体实施方式 detailed description

下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

本发明实施例中涉及到的具体化合物如下:The specific compounds involved in the embodiments of the present invention are as follows:

表1Ia系列化合物Table 1Ia series compounds

表2Ib系列化合物Table 2Ib series compounds

化合物18 Compound 18

化合物19 Compound 19

制备实施例:Preparation Examples:

以下各实施例中:In each of the following examples:

薄层层析(TLC):硅胶HSGF254(烟台市芝罘黄务硅胶开发实验厂)Thin layer chromatography (TLC): Silica gel HSGF254 (Yantai Zhifu Huangwu Silica Gel Development and Experimental Factory)

显色:紫外光(254nm、365nm)及显色剂(1g硫酸铈,2.5g钼酸钠和10%硫酸溶液配成100ml)显色Color development: ultraviolet light (254nm, 365nm) and color development agent (100ml of 1g cerium sulfate, 2.5g sodium molybdate and 10% sulfuric acid solution)

柱层析硅胶:薄层层析硅胶H(青岛海洋化工有限公司产品)Column chromatography silica gel: TLC silica gel H (product of Qingdao Ocean Chemical Co., Ltd.)

NMR:Varian-Inova-400型核磁共振仪NMR: Varian-Inova-400 Nuclear Magnetic Resonance Apparatus

MS:MAT212磁式质谱仪MS: MAT212 magnetic mass spectrometer

IR:NEXUS-670型红外光谱仪,溴化钾压片法IR: NEXUS-670 infrared spectrometer, potassium bromide tablet method

HPLC:Agilentl100GC和紫外吸收检测仪HPLC: Agilentl100GC and UV absorption detector

英文缩写说明Description of English abbreviations

实施例1乙酸肼(中间体1)Embodiment 1 hydrazine acetate (intermediate 1)

在100ml圆底烧瓶中加入85%水合肼(28.5ml,0.5mol),冰浴搅拌,缓慢滴加冰乙酸(28.6ml,0.5mol),控制温度在0-10℃。滴加完毕,室温搅拌反应40min。减压蒸馏去除水份后,剩余液体中加入氯仿∶乙醇溶液(1∶1,20ml),冰浴搅拌结晶,后再置于4℃冰箱进一步结晶,减压蒸干,得白色固体(41.6g,90.5%)。Add 85% hydrazine hydrate (28.5ml, 0.5mol) into a 100ml round bottom flask, stir in an ice bath, slowly add glacial acetic acid (28.6ml, 0.5mol) dropwise, and control the temperature at 0-10°C. After the dropwise addition was completed, the reaction was stirred at room temperature for 40 min. After removing the water by distillation under reduced pressure, chloroform:ethanol solution (1:1, 20ml) was added to the remaining liquid, stirred and crystallized in an ice bath, then placed in a refrigerator at 4°C for further crystallization, and evaporated to dryness under reduced pressure to obtain a white solid (41.6g , 90.5%).

实施例29-腙克拉霉素(中间体2)Embodiment 29-hydrazone clarithromycin (intermediate 2)

取乙酸肼(37g,0.4mol)和克拉霉素(10g,13.36mmol)于圆底烧瓶中,加入甲醇(80ml),加热回流46h。减压蒸馏,后加入水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色固体(9.68g,95.1%)。Take hydrazine acetate (37g, 0.4mol) and clarithromycin (10g, 13.36mmol) in a round bottom flask, add methanol (80ml), and heat to reflux for 46h. Distilled under reduced pressure, then added water and dichloromethane, adjusted the pH to 9.7 with 3N NaOH, separated the organic phase, extracted the water phase three times with dichloromethane, combined the organic phases, washed with water, washed with saturated saline, and dried over anhydrous sodium carbonate. After filtration, the filtrate was evaporated to dryness under reduced pressure to obtain a white solid (9.68 g, 95.1%).

实施例32’-O-乙酰基-9-乙酰基腙克拉霉素(中间体3)Example 32'-O-acetyl-9-acetylhydrazone clarithromycin (intermediate 3)

9-腙克拉霉素(3.00g,3.94mmol)溶于二氯甲烷(15mL),加入乙酸酐(1.12mL,11.85mmol),常温反应2h,加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色泡状物(3.28g,98.5%)。(小量试验过用乙酸酐和乙酸+DCC与9-腙克拉霉素反应过程和反应产物相同,故放大反应时用乙酸酐和9-腙克拉霉素反应,较方便)9-Hydrazone clarithromycin (3.00g, 3.94mmol) was dissolved in dichloromethane (15mL), added acetic anhydride (1.12mL, 11.85mmol), reacted at room temperature for 2h, added water, adjusted the pH to 9.7 with 3N NaOH, separated the organic phase, The aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium carbonate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a white foam (3.28g, 98.5%). (A small amount of tests have been conducted with acetic anhydride and acetic acid+DCC and 9-hydrazone clarithromycin for the same reaction process and reaction products, so it is more convenient to use acetic anhydride and 9-hydrazone clarithromycin for the reaction in the scale-up reaction)

MS(ESI+,m/e):846.52[M+H]+ MS (ESI + , m/e): 846.52[M+H] +

实施例49-乙酰基腙克拉霉素(化合物1)Example 49-Acetylhydrazone clarithromycin (compound 1)

2’-O-乙酰基-9-乙酰基腙克拉霉素(中间体3)(1.00g,1.18mmol)溶于甲醇(5mL),加热回流6h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[乙酸乙酯∶石油醚∶二乙胺(5∶12∶1)],得淡黄色固体(0.41g,43.2%)。2'-O-acetyl-9-acetylhydrazone clarithromycin (intermediate 3) (1.00g, 1.18mmol) was dissolved in methanol (5mL), heated to reflux for 6h, evaporated to dryness under reduced pressure, added water and dichloromethane , adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure, column chromatography Separation [ethyl acetate: petroleum ether: diethylamine (5:12:1)] gave a light yellow solid (0.41 g, 43.2%).

MS(ESI+,m/e):804.51[M+H]+ MS (ESI + , m/e): 804.51[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):8.58(s,1H,9=N-NH-),2.19(s,3H,9-CO-CH3) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 8.58 (s, 1H, 9=N-NH-), 2.19 (s, 3H, 9-CO-CH 3 )

13CNMR(400MHz,CDCl3)δ(ppm):172.56(9-NH-CO-),166.92(9>C=N-) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 172.56 (9-NH-CO-), 166.92 (9>C=N-)

实施例52’-O-苯甲酰基-9-苯甲酰基腙克拉霉素(中间体4)Example 5 2'-O-benzoyl-9-benzoylhydrazone clarithromycin (intermediate 4)

苯苯甲酸(4.00g,32.75mmol)和DCC(7.00g,33.93mmol)溶于二氯甲烷(50mL),常温反应30min,加入9-腙克拉霉素(5.00g,6.56mmol),常温反应60h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色粗产物(9.35g,含有部分二环己基脲,下同)。Benzoic acid (4.00g, 32.75mmol) and DCC (7.00g, 33.93mmol) were dissolved in dichloromethane (50mL), reacted at room temperature for 30min, added 9-hydrazone clarithromycin (5.00g, 6.56mmol), and reacted at room temperature for 60h . Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporate to dryness under reduced pressure to obtain a white crude product (9.35 g, containing part of dicyclohexyl urea, the same below).

MS(ESI+,m/e):970.56[M+H]+ MS (ESI + , m/e): 970.56[M+H] +

实施例69-苯甲酰基腙克拉霉素(化合物2)Example 69-benzoylhydrazone clarithromycin (compound 2)

上述2’-O-苯甲酰基-9-苯甲酰基腙克拉霉素粗品(中间体4,1.50g,1.05mmol)溶于甲醇(6mL),加热回流2.5h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[乙酸乙酯∶石油醚∶二乙胺(5∶7∶0.6)],得白色泡状物(0.40g,从中间体2到中间体4,最后到化合物2的总收率为44.0%)。The above crude 2'-O-benzoyl-9-benzoylhydrazone clarithromycin (Intermediate 4, 1.50g, 1.05mmol) was dissolved in methanol (6mL), heated to reflux for 2.5h, evaporated to dryness under reduced pressure, and added water Adjust the pH to 9.7 with dichloromethane and 3N NaOH, stir for 10 min, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry over anhydrous sodium carbonate, filter, and reduce the filtrate to Evaporate to dryness under pressure, and separate by column chromatography [ethyl acetate: petroleum ether: diethylamine (5:7:0.6)] to obtain a white foam (0.40 g, from intermediate 2 to intermediate 4, and finally to compound 2 The overall yield was 44.0%).

MS(ESI+,m/e):866.47[M+H]+ MS (ESI + , m/e): 866.47[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):11.69(s,1H,9=N-NH-),7.40-7.90(m,5H,9位苯环) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 11.69 (s, 1H, 9=N-NH-), 7.40-7.90 (m, 5H, 9-position benzene ring)

13CNMR(400MHz,CDCl3)δ(ppm):166.41(9-NH-CO-),163.30(9>C=N-),127.21-134.38(9位苯环上的6个碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 166.41 (9-NH-CO-), 163.30 (9>C=N-), 127.21-134.38 (6 carbons on the 9-position benzene ring)

实施例72’-O-苯甲酰基-3-O-脱克拉定糖-3-羟基-9-苯甲酰基腙克拉霉素(中间体5)Example 7 2'-O-benzoyl-3-O-declarinose-3-hydroxyl-9-benzoylhydrazone clarithromycin (intermediate 5)

上述2’-O-苯甲酰基-9-苯甲酰基腙克拉霉素粗品(中间体4,2.00g,1.40mmol)溶于1%盐酸乙醇溶液(20mL),常温反应12h,加水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色固体(1.66g)。The above crude 2'-O-benzoyl-9-benzoylhydrazone clarithromycin (intermediate 4, 2.00g, 1.40mmol) was dissolved in 1% hydrochloric acid ethanol solution (20mL), reacted at room temperature for 12h, added water and dichloro methane and 3N NaOH to adjust the pH to 9.7, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a white Solid (1.66g).

MS(ESI+,m/e):812.46[M+H]+ MS (ESI + , m/e): 812.46[M+H] +

实施例82’-O-苯甲酰基-3-O-脱克拉定糖-3-氧代-9-苯甲酰基腙克拉霉素(中间体6)Example 8 2'-O-benzoyl-3-O-declarinose-3-oxo-9-benzoylhydrazone clarithromycin (intermediate 6)

上述2’-O-苯甲酰基-3-O-脱克拉定糖-3-羟基-9-苯甲酰基腙克拉霉素粗品(中间体5,1.66g,1.40mmol)和EDC·HCl(2.63g,13.71mmol)溶于无水二氯甲烷(17mL),加入DMSO(2.62mL,36.84mmol),缓慢滴加TFA·Py(1.31g,6.75mmol)的二氯甲烷溶液,N2保护下常温反应1h,加入水,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色固体(1.66g)。The crude 2'-O-benzoyl-3-O-desclardinose-3-hydroxy-9-benzoylhydrazone clarithromycin (intermediate 5, 1.66 g, 1.40 mmol) and EDC·HCl (2.63 g, 13.71mmol) was dissolved in anhydrous dichloromethane (17mL), DMSO (2.62mL, 36.84mmol) was added, and the dichloromethane solution of TFA·Py (1.31g, 6.75mmol) was slowly added dropwise, and N2 was protected at room temperature React for 1h, add water, stir for 10min, separate the organic phase, extract the water phase with dichloromethane three times, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain White solid (1.66g).

MS(ESI+,m/e):810.45[M+H]+ MS (ESI + , m/e): 810.45[M+H] +

实施例93-O-脱克拉定糖-3-氧代-9-苯甲酰基腙克拉霉素(化合物11)Example 93-O-declarinose-3-oxo-9-benzoylhydrazone clarithromycin (compound 11)

上述2’-O-苯甲酰基-3-O-脱克拉定糖-3-氧代-9-苯甲酰基腙克拉霉素粗品(中间体6,1.66g,1.40mmol)溶于甲醇(9mL),加热回流2h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[乙酸乙酯∶石油醚∶二乙胺(5∶8∶0.6)],得淡黄色泡状物(0.56g,从中间体2,到中间体4,5,6,最后到化合物11的总收率为56.6%)。The above crude 2'-O-benzoyl-3-O-desclardinose-3-oxo-9-benzoylhydrazone clarithromycin (Intermediate 6, 1.66g, 1.40mmol) was dissolved in methanol (9mL ), heated to reflux for 2h, evaporated to dryness under reduced pressure, added water and dichloromethane, adjusted the pH to 9.7 with 3N NaOH, stirred for 10min, separated the organic phase, and extracted the aqueous phase three times with dichloromethane, combined the organic phases, washed with water, saturated Wash with brine, dry over anhydrous sodium carbonate, filter, evaporate the filtrate to dryness under reduced pressure, and separate by column chromatography [ethyl acetate:petroleum ether:diethylamine (5:8:0.6)] to obtain a light yellow foam (0.56g , from Intermediate 2, to Intermediates 4, 5, 6, and finally to Compound 11, the overall yield was 56.6%).

MS(ESI+,m/e):706.57[M+H]+ MS(ESI + , m/e): 706.57[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):11.63(s,1H,9=N-NH),7.41-7.86(m,5H,9位苯环) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 11.63 (s, 1H, 9=N-NH), 7.41-7.86 (m, 5H, 9-position benzene ring)

13CNMR(400MHz,CDCl3)δ(ppm):202.32.72(3>C=O),165.34(9-NH-CO-),163.32(9>C=N-),104.39-134.23(9位侧链苯环上的6个碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 202.32.72 (3>C=O), 165.34 (9-NH-CO-), 163.32 (9>C=N-), 104.39-134.23 (9 6 carbons on the side chain benzene ring)

实施例102’-O-对硝基苯甲酰基-9-对硝基苯甲酰基腙克拉霉素(中间体7)Example 10 2'-O-p-nitrobenzoyl-9-p-nitrobenzoylhydrazone clarithromycin (intermediate 7)

将对硝基苯甲酸(3.29g,19.69mmol)和DCC(4.22g,20.45mmol)溶于二氯甲烷(30mL),,常温反应30min,加入9-腙克拉霉素(3.00g,3.94mmol),常温反应1h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得黄色粗产物(4.54g)。Dissolve p-nitrobenzoic acid (3.29g, 19.69mmol) and DCC (4.22g, 20.45mmol) in dichloromethane (30mL), react at room temperature for 30min, add 9-hydrazone clarithromycin (3.00g, 3.94mmol) , reaction at room temperature for 1h. Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure to obtain a yellow crude product (4.54 g).

MS(ESI+,m/e):1060.53[M+H]+ MS(ESI + , m/e): 1060.53[M+H] +

实施例119-对硝基苯甲酰基腙克拉霉素(化合物3)Example 119-p-nitrobenzoylhydrazone clarithromycin (compound 3)

上述2’-O-对硝基苯甲酰基-9-对硝基苯甲酰基腙克拉霉素粗品(中间体7,1.30g,1.13mmol)溶于甲醇(6.50mL),加热回流1h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析[乙酸乙酯∶石油醚∶二乙胺(5∶4∶0.4)],得黄色泡状物(0.27g,从中间体2,到中间体7,最后到化合物3的总收率为26.5%)。The above 2'-O-p-nitrobenzoyl-9-p-nitrobenzoylhydrazone clarithromycin crude product (Intermediate 7, 1.30g, 1.13mmol) was dissolved in methanol (6.50mL), heated to reflux for 1h, and Evaporate under pressure, add water and dichloromethane, adjust the pH to 9.7 with 3N NaOH, stir for 10 minutes, separate the organic phase, extract the water phase with dichloromethane three times, combine the organic phases, wash with water, wash with saturated brine, and anhydrous sodium carbonate Drying, filtration, the filtrate was evaporated to dryness under reduced pressure, column chromatography [ethyl acetate: petroleum ether: diethylamine (5:4:0.4)], a yellow foam (0.27g, from intermediate 2 to intermediate 7. Finally, the total yield to compound 3 was 26.5%).

MS(ESI+,m/e):911.20[M+H]+ MS (ESI + , m/e): 911.20[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):8.24(s,1H,9=N-NH),8.02-8.29(m,4H,9位苯环) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 8.24 (s, 1H, 9=N-NH), 8.02-8.29 (m, 4H, 9-position benzene ring)

13CNMR(400MHz,CDCl3)δ(ppm):149.24(9-NH-CO-),128.64(9>C=N-),123.20-123.70(9位侧链苯环上的6个碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 149.24 (9-NH-CO-), 128.64 (9>C=N-), 123.20-123.70 (6 carbons on the 9-position side chain benzene ring)

实施例122’-O-对硝基苯甲酰基-3-O-脱克拉定糖-3-羟基-9-对硝基苯甲酰基腙克拉霉素(中间体8)Example 12 2'-O-p-nitrobenzoyl-3-O-descladinose-3-hydroxyl-9-p-nitrobenzoylhydrazone clarithromycin (intermediate 8)

上述2’-O-对硝基苯甲酰基-9-对硝基苯甲酰基腙克拉霉素粗品(中间体7,2.00g,1.73mmol)溶于1%盐酸乙醇溶液(20mL),常温反应7h,加水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得黄色固体(1.70g)。The above crude 2'-O-p-nitrobenzoyl-9-p-nitrobenzoylhydrazone clarithromycin (intermediate 7, 2.00g, 1.73mmol) was dissolved in 1% hydrochloric acid ethanol solution (20mL), and reacted at room temperature 7h, add water and dichloromethane, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry over anhydrous sodium carbonate, filter, and reduce the filtrate to Evaporate under pressure to obtain a yellow solid (1.70g).

MS(ESI+,m/e):902.43[M+H]+ MS(ESI + , m/e): 902.43[M+H] +

实施例132’-O-对硝基苯甲酰基-3-O-脱克拉定糖-3-氧代-9-对硝基苯甲酰基腙克拉霉素(中间体9)Example 13 2'-O-p-nitrobenzoyl-3-O-descladinose-3-oxo-9-p-nitrobenzoylhydrazone clarithromycin (intermediate 9)

上述2’-O-对硝基苯甲酰基-3-O-脱克拉定糖-3-羟基-9-对硝基苯甲酰基腙克拉霉素粗品(中间体8,1.70g,1.73mmol)和EDC·HCl(2.42g,12.64mmol)溶于无水二氯甲烷(17mL),加入DMSO(2.42mL,34.02mmol),缓慢滴加TFA·Py(1.20g,6.24mmol)的二氯甲烷溶液,N2保护下常温反应1h,加入水,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得黄色固体(1.69g)。The crude product of 2'-O-p-nitrobenzoyl-3-O-descladinose-3-hydroxy-9-p-nitrobenzoylhydrazone clarithromycin (intermediate 8, 1.70g, 1.73mmol) Dissolve EDC·HCl (2.42g, 12.64mmol) in anhydrous dichloromethane (17mL), add DMSO (2.42mL, 34.02mmol), slowly add dropwise a solution of TFA·Py (1.20g, 6.24mmol) in dichloromethane , reacted at room temperature under N2 protection for 1h, added water, stirred for 10min, separated the organic phase, extracted the water phase three times with dichloromethane, combined the organic phases, washed with water, washed with saturated saline, dried over anhydrous sodium carbonate, filtered, and the filtrate Evaporated to dryness under reduced pressure to obtain a yellow solid (1.69 g).

MS(ESI+,m/e):900.42[M+H]+ MS(ESI + , m/e): 900.42[M+H] +

实施例143-O-脱克拉定糖-3-氧代-9-对硝基苯甲酰基腙克拉霉素(化合物12)Example 143-O-declidine sugar-3-oxo-9-p-nitrobenzoylhydrazone clarithromycin (compound 12)

上述2’-O-对硝基苯甲酰基-3-O-脱克拉定糖-3-氧代-9-对硝基苯甲酰基腙克拉霉素粗品(中间体9,1.69g,1.73mmol)溶于甲醇(9mL),加热回流2h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[甲醇∶氯仿(1∶3)],得棕黄色泡状物(0.32g,从中间体2,到中间体7,8,9,最后到化合物12的总收率为24.6%)。The crude 2'-O-p-nitrobenzoyl-3-O-descladinose-3-oxo-9-p-nitrobenzoylhydrazone clarithromycin mentioned above (Intermediate 9, 1.69g, 1.73mmol ) was dissolved in methanol (9mL), heated to reflux for 2h, evaporated to dryness under reduced pressure, added water and dichloromethane, 3N NaOH to adjust the pH to 9.7, stirred for 10min, separated the organic phase, extracted the aqueous phase three times with dichloromethane, combined the organic phase, washed with water, washed with saturated brine, dried over anhydrous sodium carbonate, filtered, and the filtrate was evaporated to dryness under reduced pressure, and separated by column chromatography [methanol: chloroform (1:3)] to obtain a brown-yellow foam (0.32g, from Body 2, to intermediates 7, 8, 9, and finally to compound 12, the total yield was 24.6%).

MS(ESI+,m/e):751.31[M+H]+ MS (ESI + , m/e): 751.31 [M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):11.90(s,1H,9=N-NH),7.98-8.25(m,4H,9位苯环) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 11.90 (s, 1H, 9=N-NH), 7.98-8.25 (m, 4H, 9-position benzene ring)

13CNMR(400MHz,CDCl3)δ(ppm):202.2(3>C=O),168.0(9-NH-CO-),160.3(9>C=N-),123.39-149.56(9位侧链苯环上的6个碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 202.2 (3>C=O), 168.0 (9-NH-CO-), 160.3 (9>C=N-), 123.39-149.56 (9 side chain 6 carbons on the benzene ring)

实施例152’-O-对氯苯甲酰基-9-对氯苯甲酰基腙克拉霉素(中间体10)Example 15 2'-O-p-chlorobenzoyl-9-p-chlorobenzoylhydrazone clarithromycin (intermediate 10)

将对氯苯甲酸(3.08g,19.67mmol)和DCC(4.22g,20.45mmol)溶于二氯甲烷(30mL),常温反应30min,加入9-腙克拉霉素(3.00g,3.94mmol),常温反应24h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色粗产物(6.02g)。Dissolve p-chlorobenzoic acid (3.08g, 19.67mmol) and DCC (4.22g, 20.45mmol) in dichloromethane (30mL), react at room temperature for 30min, add 9-hydrazone clarithromycin (3.00g, 3.94mmol), and Reaction 24h. Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure to give a white crude product (6.02g).

MS(ESI+,m/e):1038.48[M+H]+ MS(ESI + , m/e): 1038.48[M+H] +

实施例169-对氯苯甲酰基腙克拉霉素(化合物4)Example 169-p-chlorobenzoylhydrazone clarithromycin (compound 4)

上述2’-O-对氯苯甲酰基-9-对氯苯甲酰基腙克拉霉素粗品(中间体10,2.00g,1.31mmol)溶于甲醇(10mL),加热回流5h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析[乙酸乙酯∶石油醚∶二乙胺(5∶7.5∶0.6)],得淡黄色固体(0.45g,从中间体2,到中间体10,最后到化合物4的总收率为38.4%)。The above crude 2'-O-p-chlorobenzoyl-9-p-chlorobenzoylhydrazone clarithromycin (intermediate 10, 2.00g, 1.31mmol) was dissolved in methanol (10mL), heated to reflux for 5h, and evaporated to dryness under reduced pressure , add water and dichloromethane, adjust the pH to 9.7 with 3NNaOH, stir for 10min, separate the organic phase, extract the water phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, and filter , the filtrate was evaporated to dryness under reduced pressure, and column chromatography [ethyl acetate: petroleum ether: diethylamine (5: 7.5: 0.6)] gave a light yellow solid (0.45 g, from intermediate 2 to intermediate 10, and finally to The overall yield of compound 4 was 38.4%).

MS(ESI+,m/e):900.40[M+H]+ MS(ESI + , m/e): 900.40[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):11.74(s,1H,9=N-NH),7.80(d,J=8Hz,2H,9位苯环3,5-H),7.39(d,J=8.4Hz,2H,9位苯环2,6-H) 1 HNMR (400MHz, CDCl 3 )δ(ppm): 11.74(s, 1H, 9=N-NH), 7.80(d, J=8Hz, 2H, 9-position benzene ring 3, 5-H), 7.39(d , J=8.4Hz, 2H, 9-position benzene ring 2, 6-H)

13CNMR(400MHz,CDCl3)δ(ppm):167.06(9-NH-CO-),162.25(9>C=N-),128.63-156.93(9位侧链苯环上的6个碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 167.06 (9-NH-CO-), 162.25 (9>C=N-), 128.63-156.93 (6 carbons on the 9-position side chain benzene ring)

实施例172’-O-对氯苯甲酰基-3-O-脱克拉定糖-3-羟基-9-对氯苯甲酰基腙克拉霉素(中间体11)Example 17 2'-O-p-chlorobenzoyl-3-O-descladinose-3-hydroxyl-9-p-chlorobenzoylhydrazone clarithromycin (intermediate 11)

上述2’-O-对氯苯甲酰基-9-对氯苯甲酰基腙克拉霉素粗品(中间体10,2.00g,1.31mmol)溶于1%盐酸乙醇溶液(20mL),常温反应17h,加水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色固体(1.68g)。The crude 2'-O-p-chlorobenzoyl-9-p-chlorobenzoylhydrazone clarithromycin (intermediate 10, 2.00 g, 1.31 mmol) was dissolved in 1% hydrochloric acid ethanol solution (20 mL), and reacted at room temperature for 17 h. Add water and dichloromethane, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate under reduced pressure Drying gave a white solid (1.68g).

MS(ESI+,m/e):880.38[M+H]+ MS (ESI + , m/e): 880.38[M+H] +

实施例182’-O-对氯苯甲酰基-3-O-脱克拉定糖-3-氧代-9-对氯苯甲酰基腙克拉霉素(中间体12)Example 18 2'-O-p-chlorobenzoyl-3-O-descladinose-3-oxo-9-p-chlorobenzoylhydrazone clarithromycin (intermediate 12)

上述2’-O-对氯苯甲酰基-3-O-脱克拉定糖-3-羟基-9-对氯苯甲酰基腙克拉霉素粗品(中间体11,1.68g,1.31mmol)和EDC·HCl(2.45g,12.79mmol)溶于无水二氯甲烷(17mL),加入DMSO(2.44mL,34.38mmol),缓慢滴加TFA·Py(1.22g,6.30mmol)的二氯甲烷溶液,N2保护下常温反应1h,加入水,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色固体(1.66g)。The crude 2'-O-p-chlorobenzoyl-3-O-descladinose-3-hydroxy-9-p-chlorobenzoylhydrazone clarithromycin (intermediate 11, 1.68 g, 1.31 mmol) and EDC HCl (2.45g, 12.79mmol) was dissolved in anhydrous dichloromethane (17mL), DMSO (2.44mL, 34.38mmol) was added, and a dichloromethane solution of TFA.Py (1.22g, 6.30mmol) was slowly added dropwise, N 2 React at room temperature under protection for 1 hour, add water, stir for 10 minutes, separate the organic phase, extract the water phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and depressurize the filtrate Evaporation to dryness gave a white solid (1.66g).

MS(ESI+,m/e):878.37[M+H]+ MS(ESI + , m/e): 878.37[M+H] +

实施例193-O-脱克拉定糖-3-氧代-9-对氯苯甲酰基腙克拉霉素(化合物13)Example 193-O-descladinose-3-oxo-9-p-chlorobenzoylhydrazone clarithromycin (compound 13)

上述2’-O-对氯苯甲酰基-3-O-脱克拉定糖-3-氧代-9-对氯苯甲酰基腙克拉霉素粗品(中间体12,1.66g,1.31mmol)溶于甲醇(9mL),加热回流2h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[甲醇∶氯仿(1∶16)],得黄色固体(0.19g,从中间体2,到中间体10,11,12,最后到化合物13的总收率为19.6%)。The crude 2'-O-p-chlorobenzoyl-3-O-descladinose-3-oxo-9-p-chlorobenzoylhydrazone clarithromycin (intermediate 12, 1.66g, 1.31mmol) was dissolved In methanol (9mL), heated to reflux for 2h, evaporated to dryness under reduced pressure, added water and dichloromethane, 3N NaOH to adjust the pH to 9.7, stirred for 10min, separated the organic phase, extracted the aqueous phase with dichloromethane three times, combined the organic phases, Washed with water, washed with saturated brine, dried over anhydrous sodium carbonate, filtered, the filtrate was evaporated to dryness under reduced pressure, and separated by column chromatography [methanol:chloroform (1:16)] to obtain a yellow solid (0.19g, from intermediate 2 to intermediate Compounds 10, 11, 12, and finally compound 13 have a total yield of 19.6%).

MS(ESI+,m/e):740.33[M+H]+ MS (ESI + , m/e): 740.33 [M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):11.7(s,1H,9=N-NH),7.37-7.78(m,4H,9位苯环) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 11.7 (s, 1H, 9=N-NH), 7.37-7.78 (m, 4H, 9-position benzene ring)

13CNMR(400MHz,CDCl3)δ(ppm):202.51(3=O),172.52(9-NH-CO-),170.14(9>C=N-),103.92-137.55(9位侧链苯环上的6个碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 202.51 (3=O), 172.52 (9-NH-CO-), 170.14 (9>C=N-), 103.92-137.55 (9 side chain benzene ring 6 carbons on

实施例202’-O-苯乙酰基-9-苯乙酰基腙克拉霉素(中间体13)Example 20 2'-O-phenylacetyl-9-phenylacetylhydrazone clarithromycin (intermediate 13)

将苯乙酸(5.36g,39.37mmol)和DCC(8.93g,43.28mmol)溶于二氯甲烷(60mL),常温反应30min,加入9-腙克拉霉素(6.00g,7.87mmol),常温反应1h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得淡黄色粗产物(9.96g)。Dissolve phenylacetic acid (5.36g, 39.37mmol) and DCC (8.93g, 43.28mmol) in dichloromethane (60mL), react at room temperature for 30min, add 9-hydrazone clarithromycin (6.00g, 7.87mmol), and react at room temperature for 1h . Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure to obtain a light yellow crude product (9.96g).

MS(ESI+,m/e):998.59[M+H]+ MS(ESI + , m/e): 998.59[M+H] +

实施例219-苯乙酰基腙克拉霉素(化合物5)Example 219-Phenylacetylhydrazone clarithromycin (compound 5)

上述2’-O-苯乙酰基-9-苯乙酰基腙克拉霉素粗品(中间体13,4.50g,3.56mmol)溶于甲醇(23mL),加热回流2.5h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得4.45g,取1.3g柱层析[乙酸乙酯∶石油醚∶二乙胺(5∶8∶0.6)],得淡黄色泡状物(0.45g,从中间体2,到中间体13,最后到化合物5的总收率为50.0%)。The above crude 2'-O-phenylacetyl-9-phenylacetylhydrazone clarithromycin (Intermediate 13, 4.50g, 3.56mmol) was dissolved in methanol (23mL), heated to reflux for 2.5h, evaporated to dryness under reduced pressure, and added water Adjust the pH to 9.7 with dichloromethane and 3N NaOH, stir for 10 min, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry over anhydrous sodium carbonate, filter, and reduce the filtrate to Evaporate under pressure to obtain 4.45g, take 1.3g column chromatography [ethyl acetate: petroleum ether: diethylamine (5:8:0.6)], obtain light yellow foam (0.45g, from intermediate 2, to The overall yield of intermediate 13 and finally compound 5 was 50.0%).

MS(ESI+,m/e):880.51[M+H]+ MS(ESI + , m/e): 880.51[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):8.58(s,1H,9=N-NH),7.22-7.36(m,5H,9位苯环),4.54(s,2H,9-CO-CH2-) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 8.58 (s, 1H, 9=N-NH), 7.22-7.36 (m, 5H, 9-position benzene ring), 4.54 (s, 2H, 9-CO- CH 2 -)

13CNMR(400MHz,CDCl3)δ(ppm):172.56(9-NH-CO-),166.92(9>C=N-),126.74-129.30(9位侧链苯环上的6个碳),32.75(9位侧链酰基与苯环之间的碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 172.56 (9-NH-CO-), 166.92 (9>C=N-), 126.74-129.30 (6 carbons on the 9-position side chain benzene ring), 32.75 (the carbon between the 9-position side chain acyl group and the benzene ring)

实施例222’-O-苯乙酰基-3-O-脱克拉定糖-3-羟基-9-苯乙酰基腙克拉霉素(中间体14)Example 22 2'-O-phenylacetyl-3-O-desclardinose-3-hydroxyl-9-phenylacetylhydrazone clarithromycin (intermediate 14)

上述2’-O-苯乙酰基-9-苯乙酰基腙克拉霉素粗品(中间体13,1.73g,1.37mmol)溶于1%盐酸乙醇溶液(17mL),常温反应21h,加水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色泡状物(1.44g)。The above crude 2'-O-phenylacetyl-9-phenylacetylhydrazone clarithromycin (intermediate 13, 1.73g, 1.37mmol) was dissolved in 1% hydrochloric acid ethanol solution (17mL), reacted at room temperature for 21h, added water and dichloro methane and 3N NaOH to adjust the pH to 9.7, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a white Bubble (1.44g).

MS(ESI+,m/e):840.49[M+H]+ MS(ESI + , m/e): 840.49[M+H] +

实施例232’-O-苯乙酰基-3-O-脱克拉定糖-3-氧代-9-苯乙酰基腙克拉霉素(中间体15)Example 23 2'-O-phenylacetyl-3-O-declarinose-3-oxo-9-phenylacetylhydrazone clarithromycin (intermediate 15)

上述2’-O-苯乙酰基-3-O-脱克拉定糖-3-羟基-9-苯乙酰基腙克拉霉素粗品(中间体14,1.44g,1.37mmol)和EDC·HCl(2.20g,11.50mmol)溶于无水二氯甲烷(15mL),加入DMSO(2.19mL,30.89mmol),缓慢滴加TFA·Py(1.09g,5.66mmol)的二氯甲烷溶液,N2保护下常温反应1h,加入水,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得黄色固体(1.30g)。The crude 2'-O-phenylacetyl-3-O-desclardinose-3-hydroxy-9-phenylacetylhydrazone clarithromycin (intermediate 14, 1.44 g, 1.37 mmol) and EDC·HCl (2.20 g, 11.50mmol) was dissolved in anhydrous dichloromethane (15mL), DMSO (2.19mL, 30.89mmol) was added, and a dichloromethane solution of TFA·Py (1.09g, 5.66mmol) was slowly added dropwise, and N2 was protected at room temperature React for 1h, add water, stir for 10min, separate the organic phase, extract the water phase with dichloromethane three times, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain Yellow solid (1.30 g).

MS(ESI+,m/e):838.48[M+H]+ MS (ESI + , m/e): 838.48[M+H] +

实施例243-O-脱克拉定糖-3-氧代-9-苯乙酰基腙克拉霉素(化合物14)Example 243-O-desclardinose-3-oxo-9-phenylacetylhydrazone clarithromycin (compound 14)

上述2’-O-苯乙酰基-3-O-脱克拉定糖-3-氧代-9-苯乙酰基腙克拉霉素粗品(中间体15,1.30g,1.37mmol)溶于甲醇(8mL),加热回流3h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[乙酸乙酯∶石油醚∶二乙胺(5∶8∶0.6)],得淡黄色泡状物(0.40g,从中间体2,到中间体13,14,15,最后到化合物14的总收率为32.0%)。The crude 2'-O-phenylacetyl-3-O-desclardinose-3-oxo-9-phenylacetylhydrazone clarithromycin (Intermediate 15, 1.30 g, 1.37 mmol) was dissolved in methanol (8 mL ), heated to reflux for 3h, evaporated to dryness under reduced pressure, added water and dichloromethane, adjusted the pH to 9.7 with 3N NaOH, stirred for 10min, separated the organic phase, and extracted the aqueous phase three times with dichloromethane, combined the organic phases, washed with water, saturated Wash with brine, dry over anhydrous sodium carbonate, filter, evaporate the filtrate to dryness under reduced pressure, and separate by column chromatography [ethyl acetate:petroleum ether:diethylamine (5:8:0.6)] to obtain a light yellow foam (0.40g , from Intermediate 2, to Intermediates 13, 14, 15, and finally to Compound 14, the overall yield was 32.0%).

MS(ESI+,m/e):720.41[M+H]+ MS(ESI + , m/e): 720.41[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):10.66(s,1H,9=N-N-H),7.21-7.30(m,5H,9位苯环),2.55(s,2H,9-CO-CH2-Ph) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 10.66 (s, 1H, 9=NNH), 7.21-7.30 (m, 5H, 9-position benzene ring), 2.55 (s, 2H, 9-CO-CH 2 -Ph)

13CNMR(400MHz,CDCl3)δ(ppm):205.79(3=O),172.33(9-NH-CO-),167.18(9>C=N-),104.30-134.40(9位侧链苯环上的6个碳),38.29(9位侧链酰基与苯环之间的碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 205.79 (3=O), 172.33 (9-NH-CO-), 167.18 (9>C=N-), 104.30-134.40 (9 side chain benzene ring 6 carbons above), 38.29 (the carbon between the 9 side chain acyl group and the benzene ring)

实施例252’-O-β-苯丙酰基-9-β-苯丙酰基腙克拉霉素(中间体16)Example 25 2'-O-β-phenylpropionyl-9-β-phenylpropionylhydrazone clarithromycin (intermediate 16)

将β-苯丙酸(5.90g,39.29mmol)和DCC(8.45g,40.95mmol)溶于二氯甲烷(60mL),常温反应30min,加入9-腙克拉霉素(6.00g,7.87mmol),常温反应24h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得淡黄色粗产物(10.29g)。Dissolve β-phenylpropionic acid (5.90g, 39.29mmol) and DCC (8.45g, 40.95mmol) in dichloromethane (60mL), react at room temperature for 30min, add 9-hydrazone clarithromycin (6.00g, 7.87mmol), Reaction at room temperature for 24h. Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure to obtain a pale yellow crude product (10.29 g).

MS(ESI+,m/e):1026.62[M+H]+ MS(ESI + , m/e): 1026.62[M+H] +

实施例269-β-苯丙酰基腙克拉霉素(化合物6)Example 269-β-phenylpropionylhydrazone clarithromycin (compound 6)

上述2’-O-β-苯丙酰基-9-β-苯丙酰基腙克拉霉素粗品(中间体16,2.19g,1.67mmol)溶于甲醇(10mL),加热回流5h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析[乙酸乙酯∶石油醚∶二乙胺(5∶10∶0.6)],得淡黄色泡状物(0.61g,从中间体2,到中间体16,最后到化合物6的总收率为40.7%)。The above crude 2'-O-β-phenylpropionyl-9-β-phenylpropionylhydrazone clarithromycin (Intermediate 16, 2.19g, 1.67mmol) was dissolved in methanol (10mL), heated to reflux for 5h, and evaporated to dryness under reduced pressure , add water and dichloromethane, adjust the pH to 9.7 with 3NNaOH, stir for 10min, separate the organic phase, extract the water phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, and filter , the filtrate was evaporated to dryness under reduced pressure, and column chromatography [ethyl acetate: petroleum ether: diethylamine (5:10:0.6)] gave a light yellow foam (0.61g, from Intermediate 2 to Intermediate 16, Finally, the total yield to compound 6 was 40.7%).

MS(ESI+,m/e):894.27[M+H]+ MS(ESI + , m/e): 894.27[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):8.60(s,1H,9=N-NH),7.15-7.29(m,5H,9位苯环),2.7-3.1,2.2-2.5(m,4H,9-CO-CH2CH2-Ph) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 8.60 (s, 1H, 9=N-NH), 7.15-7.29 (m, 5H, 9-position benzene ring), 2.7-3.1, 2.2-2.5 (m, 4H, 9- CO -CH2CH2 - Ph)

13CNMR(400MHz,CDCl3)δ(ppm):174.03(9-NH-CO-),167.08(9>C=N-),126.01-140.93(9位侧链苯环上的6个碳),33.36、30.44(9位酰基结构与苯环之间的两个烷基碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 174.03 (9-NH-CO-), 167.08 (9>C=N-), 126.01-140.93 (6 carbons on the 9-position side chain benzene ring), 33.36, 30.44 (two alkyl carbons between the 9-position acyl structure and the benzene ring)

实施例272’-O-β-苯丙酰基-3-O-脱克拉定糖-3-羟基-9-β-苯丙酰基腙克拉霉素(中间体17)Example 27 2'-O-β-phenylpropionyl-3-O-descladinose-3-hydroxyl-9-β-phenylpropionylhydrazone clarithromycin (intermediate 17)

上述2’-O-β-苯丙酰基-9-β-苯丙酰基腙克拉霉素粗品(中间体16,2.20g,1.68mmol)溶于1%盐酸乙醇溶液(22mL),常温反应24h,滤液加水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得黄色粘状固体(1.83g)。The crude 2'-O-β-phenylpropionyl-9-β-phenylpropionylhydrazone clarithromycin (intermediate 16, 2.20 g, 1.68 mmol) was dissolved in 1% hydrochloric acid ethanol solution (22 mL), and reacted at room temperature for 24 h. Add water and methylene chloride to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with methylene chloride, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and depressurize the filtrate After evaporation to dryness, a yellow sticky solid (1.83 g) was obtained.

MS(ESI+,m/e):868.52[M+H]+ MS (ESI + , m/e): 868.52[M+H] +

实施例282’-O-β-苯丙酰基-3-O-脱克拉定糖-3-氧代-9-β-苯丙酰基腙克拉霉素(中间体18)Example 28 2'-O-β-phenylpropionyl-3-O-descladinose-3-oxo-9-β-phenylpropionylhydrazone clarithromycin (intermediate 18)

上述2’-O-β-苯丙酰基-3-O-脱克拉定糖-3-羟基-9-β-苯丙酰基腙克拉霉素粗品(中间体17,1.83g,1.68mmol)和EDC·HCl(2.71g,14.14mmol)溶于无水二氯甲烷(18mL),加入DMSO(2.70mL,37.99mmol),缓慢滴加TFA·Py(1.35g,6.97mmol)的二氯甲烷溶液,N2保护下常温反应0.5h,加入水,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得黄色粘状固体(1.82g)。The above crude 2'-O-β-phenylpropionyl-3-O-desclardinose-3-hydroxy-9-β-phenylpropionylhydrazone clarithromycin (Intermediate 17, 1.83 g, 1.68 mmol) and EDC HCl (2.71g, 14.14mmol) was dissolved in anhydrous dichloromethane (18mL), DMSO (2.70mL, 37.99mmol) was added, and a dichloromethane solution of TFA.Py (1.35g, 6.97mmol) was slowly added dropwise, N 2 React at room temperature under protection for 0.5h, add water, stir for 10min, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and reduce the filtrate to Evaporate under pressure to obtain a yellow sticky solid (1.82g).

MS(ESI+,m/e):866.51[M+H]+ MS(ESI + , m/e): 866.51[M+H] +

实施例293-O-脱克拉定糖-3-氧代-9-β-苯丙酰基腙克拉霉素(化合物15)Example 293-O-desclardinose-3-oxo-9-β-phenylpropionylhydrazone clarithromycin (compound 15)

上述2’-O-苯丙酰基-3-O-脱克拉定糖-3-氧代-9-β-苯丙酰基腙克拉霉素粗品(中间体18,1.82g,1.68mmol)溶于甲醇(9mL),加热回流3h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[乙酸乙酯∶石油醚∶二乙胺(5∶8∶0.6)],得淡黄色泡状物(0.56g,从中间体2,到中间体16,17,18,最后到化合物15的总收率为45.5%)。The above crude 2'-O-phenylpropionyl-3-O-desclardinose-3-oxo-9-β-phenylpropionylhydrazone clarithromycin (Intermediate 18, 1.82g, 1.68mmol) was dissolved in methanol (9mL), heated to reflux for 3h, evaporated to dryness under reduced pressure, added water and dichloromethane, adjusted the pH to 9.7 with 3N NaOH, stirred for 10min, separated the organic phase, extracted the aqueous phase three times with dichloromethane, combined the organic phases, and washed with water , washed with saturated brine, dried over anhydrous sodium carbonate, filtered, the filtrate was evaporated to dryness under reduced pressure, and separated by column chromatography [ethyl acetate: petroleum ether: diethylamine (5:8:0.6)] to obtain a light yellow foam ( 0.56g, the total yield from Intermediate 2, to Intermediates 16, 17, 18, and finally to Compound 15 was 45.5%).

MS(ESI+,m/e):734.05[M+H]+ MS (ESI + , m/e): 734.05[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):8.80(s,1H,9=N-NH),7.14-7.27(m,5H,9位苯环),2.50-2.90,3.0-3.3(m,4H,9-CO-CH2CH2-Ph) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 8.80 (s, 1H, 9=N-NH), 7.14-7.27 (m, 5H, 9-position benzene ring), 2.50-2.90, 3.0-3.3 (m, 4H, 9- CO -CH2CH2 - Ph)

13CNMR(400MHz,CDCl3)δ(ppm):205.81(3>C=O),169.86(9-NH-CO-),166.64(9>C=N-),126.05-140.89(9位侧链苯环上的6个碳),34.29、28.36(9位酰基结构与苯环之间的两个烷基碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 205.81 (3>C=O), 169.86 (9-NH-CO-), 166.64 (9>C=N-), 126.05-140.89 (9 side chain 6 carbons on the benzene ring), 34.29, 28.36 (two alkyl carbons between the 9-position acyl structure and the benzene ring)

实施例302’-O-肉桂酰基-9-肉桂酰基腙克拉霉素(中间19)Example 30 2'-O-cinnamoyl-9-cinnamoylhydrazone clarithromycin (middle 19)

将肉桂酸(5.83g,39.35mmol)和DCC(8.93g,43.28mmol)溶于二氯甲烷(60mL),常温反应30min,加入9-腙克拉霉素(6.00g,7.87mmol),常温反应48h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得淡黄色粗产物(11.14g)。Dissolve cinnamic acid (5.83g, 39.35mmol) and DCC (8.93g, 43.28mmol) in dichloromethane (60mL), react at room temperature for 30min, add 9-hydrazone clarithromycin (6.00g, 7.87mmol), and react at room temperature for 48h . Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure to obtain a pale yellow crude product (11.14 g).

MS(ESI+,m/e):1022.59[M+H]+ MS(ESI + , m/e): 1022.59[M+H] +

实施例319-肉桂酰基腙克拉霉素(化合物7)Example 319-Cinnamoylhydrazone Clarithromycin (Compound 7)

上述2’-O-肉桂酰基-9-肉桂酰基腙克拉霉素粗品(中间19,1.20g,0.85mmol),溶于甲醇(6mL),加热回流16h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析[乙酸乙酯∶石油醚∶二乙胺(5∶8∶O.6)],得黄色泡状物(0.67g,从中间体2,到中间体19,最后到化合物7的总收率为88.7%)。The above crude 2'-O-cinnamoyl-9-cinnamoylhydrazone clarithromycin (intermediate 19, 1.20g, 0.85mmol) was dissolved in methanol (6mL), heated to reflux for 16h, evaporated to dryness under reduced pressure, added water and dichloro Adjust the pH to 9.7 with methane and 3NNaOH, stir for 10 minutes, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure , column chromatography [ethyl acetate: petroleum ether: diethylamine (5:8:0.6)], to obtain a yellow foam (0.67g, from intermediate 2 to intermediate 19, and finally to compound 7 The overall yield was 88.7%).

MS(ESI+,m/e):892.45[M+H]+ MS(ESI + , m/e): 892.45[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):11.35(s,1H,9=N-N-H),7.25-7.80(m,5H,9位苯环),7.17(d,J=15.6Hz,1H,9=CH-Ph),6.34(d,J=15.6Hz,1H,9-CO-CH=) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 11.35 (s, 1H, 9 = NNH), 7.25-7.80 (m, 5H, 9-position benzene ring), 7.17 (d, J = 15.6Hz, 1H, 9 =CH-Ph), 6.34 (d, J=15.6Hz, 1H, 9-CO-CH=)

13CNMR(400MHz,CDCl3)δ(ppm):177.85(9-NH-CO-),167.06(9>C=N-),144.06(9=CH-Ph),117.41(9-CO-CH=),103.14-135.83(9位侧链苯环上的6个碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 177.85 (9-NH-CO-), 167.06 (9>C=N-), 144.06 (9=CH-Ph), 117.41 (9-CO-CH= ), 103.14-135.83 (6 carbons on the 9-position side chain benzene ring)

实施例322’-O-肉桂酰基-3-O-脱克拉定糖-3-羟基-9-肉桂酰基腙克拉霉素(中间体20)Example 32 2'-O-cinnamoyl-3-O-declarinose-3-hydroxyl-9-cinnamoylhydrazone clarithromycin (intermediate 20)

上述2’-O-肉桂酰基-9-肉桂酰基腙克拉霉素粗品(中间19,2.00g,1.41mmol)溶于1%盐酸乙醇溶液(20mL),常温反应24h,滤液加水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得黄色泡状物(1.68g)。The above crude 2'-O-cinnamoyl-9-cinnamoylhydrazone clarithromycin (intermediate 19, 2.00g, 1.41mmol) was dissolved in 1% hydrochloric acid ethanol solution (20mL), reacted at room temperature for 24h, and the filtrate was added with water and dichloromethane, Adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a yellow foam compound (1.68g).

MS(ESI+,m/e):864.49[M+H]+ MS (ESI + , m/e): 864.49[M+H] +

实施例332’-O-肉桂酰基-3-O-脱克拉定糖-3-氧代-9-肉桂酰基腙克拉霉素(中间体21)Example 33 2'-O-cinnamoyl-3-O-declarinose-3-oxo-9-cinnamoylhydrazone clarithromycin (intermediate 21)

上述2’-O-肉桂酰基-3-O-脱克拉定糖-3-羟基-9-肉桂酰基腙克拉霉素粗品(中间体20,1.61g,1.41mmol)和EDC·HCl(2.47g,12.50mmol)溶于无水二氯甲烷(16mL),加入DMSO(2.46mL,33.58mmol),缓慢滴加TFA·Py(1.19g,6.16mmol)的二氯甲烷溶液,N2保护下常温反应0.5h,加入水,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得黄色粘状固体(1.61g)。The crude 2'-O-cinnamoyl-3-O-desclardinose-3-hydroxy-9-cinnamoylhydrazone clarithromycin (Intermediate 20, 1.61 g, 1.41 mmol) and EDC·HCl (2.47 g, 12.50mmol) was dissolved in anhydrous dichloromethane (16mL), DMSO (2.46mL, 33.58mmol) was added, and the dichloromethane solution of TFA·Py (1.19g, 6.16mmol ) was slowly added dropwise. h, add water, stir for 10 min, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain yellow Sticky solid (1.61 g).

MS(ESI+,m/e):862.48[M+H]+ MS (ESI + , m/e): 862.48[M+H] +

实施例343-O-脱克拉定糖-3-氧代-9-肉桂酰基腙克拉霉素(化合物16)Example 343-O-declarinose-3-oxo-9-cinnamoylhydrazone clarithromycin (compound 16)

上述2’-O-肉桂酰基-3-O-脱克拉定糖-3-氧代-9-肉桂酰基腙克拉霉素粗品(中间体21,1.61g,1.41mmol)溶于甲醇(8mL),加热回流3h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[乙酸乙酯∶石油醚∶二乙胺(5∶8∶0.6)],得黄色泡状物(0.35g,从中间体2,到中间体19,20,21,最后到化合物16的总收率为33.9%)The crude 2'-O-cinnamoyl-3-O-desclardinose-3-oxo-9-cinnamoylhydrazone clarithromycin (Intermediate 21, 1.61 g, 1.41 mmol) was dissolved in methanol (8 mL), Heat to reflux for 3 hours, evaporate to dryness under reduced pressure, add water and dichloromethane, adjust the pH to 9.7 with 3N NaOH, stir for 10 minutes, separate the organic phase, extract the water phase with dichloromethane three times, combine the organic phases, wash with water, and wash with saturated brine , dried over anhydrous sodium carbonate, filtered, the filtrate was evaporated to dryness under reduced pressure, and separated by column chromatography [ethyl acetate: petroleum ether: diethylamine (5:8:0.6)] to obtain a yellow foam (0.35g, from body 2, to intermediates 19, 20, 21, and finally to compound 16, the total yield was 33.9%)

MS(ESI+,m/e):732.41[M+H]+ MS (ESI + , m/e): 732.41 [M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):11.32(s,1H,9=N-N-H),7.73(t,J=17.6Hz,1H,9位苯环4-H),7.33-7.59(m,4H,9位苯环2,3,5,6-H,1H,9=CH-Ph),6.34(d,J=15.6Hz,1H,9-CO-CH=) 1 HNMR (400MHz, CDCl 3 )δ(ppm): 11.32(s, 1H, 9=NNH), 7.73(t, J=17.6Hz, 1H, 9-position benzene ring 4-H), 7.33-7.59(m, 4H, 9-position benzene ring 2, 3, 5, 6-H, 1H, 9=CH-Ph), 6.34 (d, J=15.6Hz, 1H, 9-CO-CH=)

13CNMR(400MHz,CDCl3)δ(ppm):202.85(3>C=O),167.06(9-NH-CO-),161.91(9>C=N-),142.14(9=CH-Ph),117.25(9-CO-CH=),120.23-135.81(9位侧链苯环上的6个碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 202.85 (3>C=O), 167.06 (9-NH-CO-), 161.91 (9>C=N-), 142.14 (9=CH-Ph) , 117.25 (9-CO-CH=), 120.23-135.81 (6 carbons on the 9-position side chain benzene ring)

实施例352’-O-(2-噻吩乙酰基)-9-(2-噻吩乙酰基)腙克拉霉素(中间体22)Example 35 2'-O-(2-thiopheneacetyl)-9-(2-thiopheneacetyl)hydrazone clarithromycin (intermediate 22)

将2-噻吩乙酸(2.80g,19.69mmol)和DCC(4.22g,20.45mmol)溶于二氯甲烷(30mL),常温反应30min,加入9-腙克拉霉素(3.00g,3.94mmol),常温反应24h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得棕色粗产物(5.19g)。Dissolve 2-thiopheneacetic acid (2.80g, 19.69mmol) and DCC (4.22g, 20.45mmol) in dichloromethane (30mL), react at room temperature for 30min, add 9-hydrazone clarithromycin (3.00g, 3.94mmol), and Reaction 24h. Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure to obtain a brown crude product (5.19 g).

MS(ESI+,m/e):1010.50[M+H]+ MS(ESI + , m/e): 1010.50[M+H] +

实施例369-(2-噻吩乙酰基)腙克拉霉素(化合物8)Example 369-(2-thiopheneacetyl)hydrazone clarithromycin (compound 8)

上述2’-O-(2-噻吩乙酰基)-9-(2-噻吩乙酰基)腙克拉霉素粗品(中间体22,1.60g,1.21mmol)溶于甲醇(8mL),加热回流2h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析[乙酸乙酯∶石油醚∶二乙胺(5∶8∶0.6)],得棕色泡状物(0.61g,从中间体2,到中间体22,最后到化合物8的总收率为57.0%)。The crude 2'-O-(2-thiopheneacetyl)-9-(2-thiopheneacetyl)hydrazone clarithromycin (Intermediate 22, 1.60 g, 1.21 mmol) was dissolved in methanol (8 mL), heated to reflux for 2 h, Evaporate to dryness under reduced pressure, add water and dichloromethane, adjust the pH to 9.7 with 3N NaOH, stir for 10 min, separate the organic phase, extract the water phase with dichloromethane three times, combine the organic phases, wash with water, wash with saturated saline, and anhydrous carbonic acid Sodium was dried, filtered, the filtrate was evaporated to dryness under reduced pressure, and column chromatography [ethyl acetate: petroleum ether: diethylamine (5:8:0.6)] gave a brown foam (0.61g, from intermediate 2 to intermediate 22, and finally the total yield to compound 8 was 57.0%).

MS(ESI+,m/e):886.31[M+H]+ MS (ESI + , m/e): 886.31[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):8.57(s,1H,9=N-NH),6.92-7.26(m,3H,9位噻吩环),4.46(s,2H,9-CO-CH2-) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 8.57 (s, 1H, 9=N-NH), 6.92-7.26 (m, 3H, 9-position thiophene ring), 4.46 (s, 2H, 9-CO- CH 2 -)

13CNMR(400MHz,CDCl3)δ(ppm):171.41(9-NH-CO-),168.21(9>C=N-),124.72-135.57(9位侧链噻吩环上的4个碳),33.88(9位酰基结构与噻吩环之间的烷基碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 171.41 (9-NH-CO-), 168.21 (9>C=N-), 124.72-135.57 (4 carbons on the 9-position side chain thiophene ring), 33.88 (the alkyl carbon between the 9-position acyl structure and the thiophene ring)

实施例372’-O-(3-吲哚乙酰基)-9-(3-吲哚乙酰基)腙克拉霉素(中间体23)Example 37 2'-O-(3-indoleacetyl)-9-(3-indoleacetyl)hydrazone clarithromycin (intermediate 23)

将3-吲哚乙酸(3.45g,19.69mmol)和DCC(4.22g,20.45mmol)溶于二氯甲烷(30mL),溶液混浊,常温反应30min,加入9-腙克拉霉素(3.00g,3.94mmol),常温反应18h。过滤,除去不溶物,滤液加水,3MNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得棕黄色粗产物(4.45g)。3-Indoleacetic acid (3.45g, 19.69mmol) and DCC (4.22g, 20.45mmol) were dissolved in dichloromethane (30mL), the solution was turbid, reacted at room temperature for 30min, added 9-hydrazone clarithromycin (3.00g, 3.94 mmol), react at room temperature for 18h. Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3M NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure to obtain a brownish yellow crude product (4.45g).

MS(ESI+,m/e):1076.61[M+H]+ MS (ESI + , m/e): 1076.61 [M+H] +

实施例389-(3-吲哚乙酰基)腙克拉霉素(化合物9)Example 389-(3-indoleacetyl)hydrazone clarithromycin (compound 9)

上述2’-O-(3-吲哚乙酰基)-9-(3-吲哚乙酰基)腙克拉霉素粗品(中间体23,1.30g,1.15mmol)溶于甲醇(6.50mL),加热回流5h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析[乙酸乙酯∶石油醚∶二乙胺(7∶5∶0.55)],得棕黄色泡状物(0.41g,从中间体2,到中间体23,最后到化合物9的总收率为39.0%)。The above crude 2'-O-(3-indoleacetyl)-9-(3-indoleacetyl)hydrazone clarithromycin (Intermediate 23, 1.30 g, 1.15 mmol) was dissolved in methanol (6.50 mL) and heated Reflux for 5 hours, evaporate to dryness under reduced pressure, add water and dichloromethane, adjust the pH to 9.7 with 3N NaOH, stir for 10 minutes, separate the organic phase, extract the water phase with dichloromethane three times, combine the organic phases, wash with water, and wash with saturated brine. Dry over anhydrous sodium carbonate, filter, evaporate the filtrate to dryness under reduced pressure, and perform column chromatography [ethyl acetate: petroleum ether: diethylamine (7:5:0.55)] to obtain brown-yellow foam (0.41g, obtained from intermediate 2, to intermediate 23, and finally to compound 9, the total yield was 39.0%).

MS(ESI+,m/e):919.51[M+H]+ MS(ESI + , m/e): 919.51[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):8.71(s,1H,9位吲哚环NH),8.48(s,1H,9=N-NH),7.64(d,1H,9位吲哚环的4-H),7.33(d,1H,9位吲哚环的7-H),7.11-7.20(m,3H,9位吲哚环的2,5,6-H),3.50(s,2H,9-CO-CH2-) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 8.71 (s, 1H, NH of the 9-position indole ring), 8.48 (s, 1H, 9=N-NH), 7.64 (d, 1H, 9-position indole ring 4-H of the ring), 7.33 (d, 1H, 7-H of the 9-position indole ring), 7.11-7.20 (m, 3H, 2, 5, 6-H of the 9-position indole ring), 3.50 (s , 2H, 9-CO-CH 2 -)

13CNMR(400MHz,CDCl3)δ(ppm):171.59(9-NH-CO-),166.57(9>C=N-),121.81-136.59(9位侧链吲哚环上的8个碳),29.78(9位酰基结构与吲哚环之间的烷基碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 171.59 (9-NH-CO-), 166.57 (9>C=N-), 121.81-136.59 (8 carbons on the 9 side chain indole ring) , 29.78 (the alkyl carbon between the 9-position acyl structure and the indole ring)

实施例392’-O-(3-吲哚丁酰基)-9-(3-吲哚丁酰基)腙克拉霉素(中间体24)Example 39 2'-O-(3-indolebutyryl)-9-(3-indolebutyryl)hydrazone clarithromycin (intermediate 24)

将3-吲哚丁酸(4.00g,19.68mmol)和DCC(4.22g,20.45mmol)溶于二氯甲烷(30mL),常温反应30min,加入9-腙克拉霉素(3.00g,3.94mmol),常温反应45h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得棕黄色固体粗产物(6.05g)。Dissolve 3-indolebutyric acid (4.00g, 19.68mmol) and DCC (4.22g, 20.45mmol) in dichloromethane (30mL), react at room temperature for 30min, add 9-hydrazone clarithromycin (3.00g, 3.94mmol) , Reaction at room temperature for 45h. Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure, the crude product (6.05 g) was obtained as a brown-yellow solid.

MS(ESI+,m/e):1132.67[M+H]+ MS (ESI + , m/e): 1132.67 [M+H] +

实施例409-(3-吲哚丁酰基)腙克拉霉素(化合物10)Embodiment 409-(3-indolebutyryl)hydrazone clarithromycin (compound 10)

上述2’-O-(3-吲哚丁酰基)-9-(3-吲哚丁酰基)腙克拉霉素粗品(中间体24,1.40g,0.91mmol)溶于甲醇(7mL),加热回流8h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析[乙酸乙酯∶石油醚∶二乙胺(5∶6∶0.5)],得黄色泡状物(0.47g,从中间体2,到中间体24,最后到化合物10的总收率为54.4%)The above crude 2'-O-(3-indolebutyryl)-9-(3-indolebutyryl)hydrazone clarithromycin (Intermediate 24, 1.40 g, 0.91 mmol) was dissolved in methanol (7 mL) and heated to reflux 8h, evaporated to dryness under reduced pressure, added water and dichloromethane, adjusted the pH to 9.7 with 3N NaOH, stirred for 10min, separated the organic phase, extracted the water phase with dichloromethane three times, combined the organic phases, washed with water, and washed with saturated brine. Dry over sodium carbonate, filter, evaporate the filtrate to dryness under reduced pressure, column chromatography [ethyl acetate:petroleum ether:diethylamine (5:6:0.5)] to obtain a yellow foam (0.47g, from intermediate 2, To intermediate 24, the total yield to compound 10 is 54.4%)

MS(ESI+,m/e):947.51[M+H]+ MS (ESI + , m/e): 947.51 [M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):8.56(s,1H,9位吲哚环NH)8.45(s,1H,9=N-NH),7.59(d,J=7.6Hz,1H,9位吲哚环的4-H),7.30(d,J=8.4Hz,1H,9位吲哚环的7-H),6.99-7.16(m,3H,9位吲哚环的2,5,6-H),2.85(t,J=7.0Hz,2H,9-CH2-吲哚环),2.0-2.63(m,4H,9位邻近酰基结构的两个CH2) 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 8.56 (s, 1H, 9-position indole ring NH) 8.45 (s, 1H, 9=N-NH), 7.59 (d, J=7.6Hz, 1H, 4-H of the 9-position indole ring), 7.30 (d, J=8.4Hz, 1H, 7-H of the 9-position indole ring), 6.99-7.16 (m, 3H, 2,5 , 6-H), 2.85 (t, J=7.0Hz, 2H, 9-CH 2 -indole ring), 2.0-2.63 (m, 4H, two CH 2 adjacent to the acyl structure at position 9)

13CNMR(400MHz,CDCl3)δ(ppm):174.92(9-NH-CO-),166.46(9>C=N-),111.02-136.56(9位侧链吲哚环上的8个碳),35.08、31.97、24.56(9位酰基结构与吲哚环之间的3个烷基碳) 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 174.92 (9-NH-CO-), 166.46 (9>C=N-), 111.02-136.56 (8 carbons on the 9 side chain indole ring) , 35.08, 31.97, 24.56 (3 alkyl carbons between the 9-position acyl structure and the indole ring)

实施例412’-O-异丁酰基-9-异丁酰基腙克拉霉素(中间25)Example 41 2'-O-isobutyryl-9-isobutyrylhydrazone clarithromycin (middle 25)

将异丁酸(2.33ml,25mmol)和DCC(4.38g,21.25mmol)溶于二氯甲烷(38mL),溶液混浊,常温反应30min,加入9-腙克拉霉素(3.81g,5.00mmol),常温反应72h。过滤,除去不溶物,滤液加水,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色粗产物(4.10g)。Dissolve isobutyric acid (2.33ml, 25mmol) and DCC (4.38g, 21.25mmol) in dichloromethane (38mL), the solution was turbid, reacted at room temperature for 30min, added 9-hydrazone clarithromycin (3.81g, 5.00mmol), Reaction at room temperature for 72h. Filter to remove insoluble matter, add water to the filtrate, adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated saline, dry with anhydrous sodium carbonate, filter, and filtrate Evaporated to dryness under reduced pressure to obtain a white crude product (4.10 g).

MS(ESI+,m/e):902.59[M+H]+ MS(ESI + , m/e): 902.59[M+H] +

实施例422’-O-异丁酰基-3-O-脱克拉定糖-3-羟基-9-异丁酰基腙克拉霉素(中间体26)Example 42 2'-O-isobutyryl-3-O-desclardinose-3-hydroxyl-9-isobutyrylhydrazone clarithromycin (intermediate 26)

上述2’-O-异丁酰基-9-异丁酰基腙克拉霉素(中间25,4.10g,5.00mmol)溶于1%盐酸乙醇溶液(20mL),常温反应24h,加水和二氯甲烷,3NNaOH调pH至9.7,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色固体(3.74g)。The above 2'-O-isobutyryl-9-isobutyrylhydrazone clarithromycin (intermediate 25, 4.10g, 5.00mmol) was dissolved in 1% hydrochloric acid ethanol solution (20mL), reacted at room temperature for 24h, added water and dichloromethane, Adjust the pH to 9.7 with 3N NaOH, separate the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a white solid ( 3.74g).

MS(ESI+,m/e):744.49[M+H]+ MS (ESI + , m/e): 744.49 [M+H] +

实施例432’-O-异丁酰基-3-O-脱克拉定糖-3-氧代-9-异丁酰基腙克拉霉素(中间体27)Example 43 2'-O-isobutyryl-3-O-desclardinose-3-oxo-9-isobutyrylhydrazone clarithromycin (intermediate 27)

上述2’-O-异丁酰基-3-O-脱克拉定糖-3-羟基-9-异丁酰基腙克拉霉素粗品(中间体26,3.24g,4.33mmol)和EDC·HCl(4.33g,22.60mmol)溶于无水二氯甲烷(30ml),加入DMSO(3.54mL,45.30mmol),缓慢滴加TFA·Py(2.61g,22.6mmol)的二氯甲烷溶液,N2保护下常温反应24h,加入水,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,得白色固体(2.22g)。The crude 2'-O-isobutyryl-3-O-desclardinose-3-hydroxy-9-isobutyrylhydrazone clarithromycin (intermediate 26, 3.24 g, 4.33 mmol) and EDC·HCl (4.33 g, 22.60mmol) was dissolved in anhydrous dichloromethane (30ml), DMSO (3.54mL, 45.30mmol) was added, and the dichloromethane solution of TFA·Py ( 2.61g , 22.6mmol) was slowly added dropwise. React for 24 hours, add water, stir for 10 minutes, separate the organic phase, extract the water phase with dichloromethane three times, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium carbonate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain White solid (2.22g).

MS(ESI+,m/e):742.48[M+H]+ MS (ESI + , m/e): 742.48[M+H] +

实施例443-O-脱克拉定糖-3-氧代-9-异丁酰基腙克拉霉素(化合物17)Example 443-O-desclardinose-3-oxo-9-isobutyrylhydrazone clarithromycin (compound 17)

上述2’-O-异丁酰基-3-O-脱克拉定糖-3-氧代-9-异丁酰基腙克拉霉素粗品(中间体27,2.22g,4.33mmol)溶于甲醇(20mL),加热回流3h,减压蒸干,加入水和二氯甲烷,3NNaOH调pH至9.7,搅拌10min,分出有机相,水相用二氯甲烷抽提三次,合并有机相,经水洗,饱和食盐水洗,无水碳酸钠干燥,过滤,滤液减压蒸干,柱层析分离[甲醇∶氯仿(1∶10)],得白色泡状物(0.45g,从中间体2,到中间体25,26,27,最后到化合物17的总收率为15.5%)。The crude 2'-O-isobutyryl-3-O-desclardinose-3-oxo-9-isobutyrylhydrazone clarithromycin (Intermediate 27, 2.22 g, 4.33 mmol) was dissolved in methanol (20 mL ), heated to reflux for 3h, evaporated to dryness under reduced pressure, added water and dichloromethane, adjusted the pH to 9.7 with 3N NaOH, stirred for 10min, separated the organic phase, and extracted the aqueous phase three times with dichloromethane, combined the organic phases, washed with water, saturated Wash with brine, dry over anhydrous sodium carbonate, filter, evaporate the filtrate to dryness under reduced pressure, and separate by column chromatography [methanol:chloroform (1:10)] to obtain a white foam (0.45g, from Intermediate 2 to Intermediate 25 , 26, 27, and finally the total yield to compound 17 was 15.5%).

MS(ESI+,m/e):672.44[M+H]+ MS (ESI + , m/e): 672.44[M+H] +

实施例459-腙硫氰酸红霉素A(中间体25)Embodiment 459-hydrazone erythromycin thiocyanate A (intermediate 25)

硫氰酸红霉素A(20g,0.0252mol)溶于甲醇(20mL),加入85%水合肼(2.2mL,0.0378mol),加热回流18h后冷却,析出固体,过滤,滤饼水洗得白色固体(13.3g,65.0%)。Erythromycin thiocyanate A (20g, 0.0252mol) was dissolved in methanol (20mL), 85% hydrazine hydrate (2.2mL, 0.0378mol) was added, heated to reflux for 18h and then cooled, a solid precipitated, filtered, and the filter cake was washed with water to obtain a white solid (13.3 g, 65.0%).

9-腙红霉素A(中间体26)9-hydrazone erythromycin A (intermediate 26)

9-腙硫氰酸红霉素A(中间体25)(4.00g,0.0050mol)溶于二氯甲烷(90mL)-水(80mL),用3mol/L氢氧化钠溶液调至pH9.7,分出有机相,水洗,无水硫酸钠干燥,过滤,减压蒸干,的白色泡状物(3.352g,90.4%)。9-hydrazone thiocyanate erythromycin A (intermediate 25) (4.00g, 0.0050mol) was dissolved in dichloromethane (90mL)-water (80mL), adjusted to pH9.7 with 3mol/L sodium hydroxide solution, The organic phase was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a white foam (3.352 g, 90.4%).

实施例46N-[4-(2,5-二氯苯氧基)-2-丁烯基]-9-腙红霉素A(化合物18)Example 46 N-[4-(2,5-dichlorophenoxy)-2-butenyl]-9-hydrazone erythromycin A (compound 18)

9-腙红霉素A(中间体26)(2.00g,0.0025mol)溶于DMF(20mL),加入无水碳酸钾(0.69g,0.0050mol)4-(2,5-二氯苯氧基)-2-丁烯-1-溴(0.96g,0.0033mol)室温下搅拌16h后加水(50mL),二氯甲烷(30mL),静置分层,分出有机相,水相用二氯甲烷抽提,合并有机相,经水洗,无水硫酸钠干燥,过滤,滤液减压蒸干,柱色谱分离[洗脱剂∶甲醇-二氯甲烷(1∶13)],得到白色固体(0.604g,25.1%)。9-hydrazone erythromycin A (intermediate 26) (2.00g, 0.0025mol) was dissolved in DMF (20mL), and anhydrous potassium carbonate (0.69g, 0.0050mol) was added to 4-(2,5-dichlorophenoxy )-2-butene-1-bromide (0.96g, 0.0033mol) was stirred at room temperature for 16h, then added water (50mL), dichloromethane (30mL), allowed to stand for layers, separated the organic phase, and used dichloromethane for the aqueous phase Extract, combine the organic phases, wash with water, dry over anhydrous sodium sulfate, filter, evaporate the filtrate to dryness under reduced pressure, and separate by column chromatography [eluent: methanol-dichloromethane (1:13)] to obtain a white solid (0.604g , 25.1%).

MS(ESI+,m/z):962[M+H]+ MS (ESI + , m/z): 962[M+H] +

1HNMR(400MHz,CDCl3)δ(ppm):7.47(d,J=8.4,1H,9-苯环3-H),7.26(d,J=2Hz,1H,9-苯环6-H),7.05(dd,1H,9-苯环4-H),6.09-δ6.32(m,2H,9-CH=CH-),5.06-5.10(dd,1H,1′-CH-)。 1 HNMR (400MHz, CDCl 3 )δ(ppm): 7.47 (d, J=8.4, 1H, 9-benzene ring 3-H), 7.26 (d, J=2Hz, 1H, 9-benzene ring 6-H) , 7.05 (dd, 1H, 9-benzene ring 4-H), 6.09-δ6.32 (m, 2H, 9-CH=CH-), 5.06-5.10 (dd, 1H, 1'-CH-).

13CNMR(400MHz,CDCl3)δ(ppm):174.7(1-CO),165.7(9-C=N-),154.1(9-苯环1-C),137.8(3-CH=CH-),132.5(9-苯环5-C),131.1(9-苯环3-C),121.8(9-苯环4-C),120.8(9-苯环6-C),114.8(9-苯环6-C),100.9(1′-CH),95.9(3-O-CH),82.7(5-CH),78.8(3-CH),77.3(4″-CH),76.1(13-CH),74.1(12-C),73.8(6-C),71.1(2′-CH),70.7(5″-CH),68.5(3-O-CH2),65.7(3′-CH),65.2(3-CH=CH-CH2),44.1(2-CH),38.0(7-CH2),35.1(4′-CH2),21.1(6-CH3),21.0(13-CH2-CH3),18.7(8-CH3),16.2(12-CH3),14.6(10-CH3),10.6(13-CH2-CH3),9.6(4-CH3)。 13 CNMR (400MHz, CDCl 3 ) δ (ppm): 174.7 (1-CO), 165.7 (9-C=N-), 154.1 (9-benzene ring 1-C), 137.8 (3 - CH=CH- ), 132.5 (9-benzene ring 5-C), 131.1 (9-benzene ring 3-C), 121.8 (9-benzene ring 4-C), 120.8 (9-benzene ring 6-C), 114.8 (9- Benzene ring 6-C), 100.9(1′-CH), 95.9(3-O-CH), 82.7(5-CH), 78.8(3-CH), 77.3(4″-CH), 76.1(13- CH), 74.1(12-C), 73.8(6-C), 71.1(2'-CH), 70.7(5"-CH), 68.5(3-O-CH 2 ), 65.7(3'-CH) , 65.2 (3-CH=CH- CH 2 ), 44.1 (2-CH), 38.0 (7-CH 2 ), 35.1 (4′-CH 2 ), 21.1 (6-CH 3 ), 21.0 (13- CH 2 -CH 3 ), 18.7(8-CH 3 ), 16.2(12-CH 3 ), 14.6(10-CH 3 ), 10.6(13- CH 2 -CH 3 ), 9.6(4-CH 3 ).

实施例47N-(2-二乙氨基乙基)-9-腙红霉素A(化合物19)Example 47 N-(2-diethylaminoethyl)-9-hydrazone erythromycin A (compound 19)

9-腙红霉素A(中间体26)(1.30g,0.0016mol)溶于无水乙醇(7mL),加入二乙氨基氯乙烷盐酸盐(0.3053g,0.0018mol),加热回流搅拌7h,加入二氯甲烷(25mL),水(20mL),pH调至9.3静置分层,分出有机相,水相用二氯甲烷抽提,合并有机相,经水洗,无水硫酸钠干燥,过滤,滤液减压蒸干,柱色谱分离[洗脱剂∶乙酸乙酯-石油醚-二乙胺(5∶16∶1)]得白色泡状物,再经柱色谱分离[洗脱剂∶甲醇-二氯甲烷-氨水(1∶25∶0.5)]得白色泡状物(0.055g,4.1%)。9-Hydrazone erythromycin A (intermediate 26) (1.30g, 0.0016mol) was dissolved in absolute ethanol (7mL), diethylaminochloroethane hydrochloride (0.3053g, 0.0018mol) was added, heated to reflux and stirred for 7h , add dichloromethane (25mL), water (20mL), adjust the pH to 9.3 and let it stand for stratification, separate the organic phase, extract the water phase with dichloromethane, combine the organic phases, wash with water, and dry over anhydrous sodium sulfate. Filtrate, evaporate the filtrate to dryness under reduced pressure, and separate by column chromatography [eluent: ethyl acetate-petroleum ether-diethylamine (5:16:1)] to obtain a white foam, which is then separated by column chromatography [eluent: Methanol-dichloromethane-ammonia water (1:25:0.5)] to obtain a white foam (0.055g, 4.1%).

MS(ESI+,m/z):847[M+H]+ MS (ESI + , m/z): 847[M+H] +

1HNMR(400MHz,DMSO)δ(ppm):5.57(s,1H,9-N-NH-),5.08-5.11(dd,1H,1′-CH-),2.32-2.64(m,8H,9-NH-CH 2 CH 2 N(CH 2 CH3)2)。 1 HNMR (400MHz, DMSO) δ (ppm): 5.57 (s, 1H, 9-N-NH-), 5.08-5.11 (dd, 1H, 1'-CH-), 2.32-2.64 (m, 8H, 9 -NH - CH2CH2N (CH2CH3 ) 2 ) .

13CNMR(400MHz,DMSO)δ(ppm):174.7(1-CO),δ165.7(9-C=N-),102.9(1′-CH),96.4(3-O-CH),83.7(5-CH),80.4(3-CH),78.1(4″-CH),77.3(12-C),77.0(6-C),76.8(13-CH),76.7(5″-CH),71.5(2′-CH),65.5(3′-CH),51.6(9-NH-CH2 CH2N),48.0(9-NH-CH2CH2N),45.6(9-NH-CH2CH2N(CH 2 CH3)2),44.7(2-CH),40.3(3′-N(CH3)2),38.7(7-CH2),35.2(6″-CH),32.6(4-CH),28.9(4′-CH2),21.5(6-CH3),21.1(13-CH2-CH3),18.6(8-CH3),16.0(12-CH3),14.3(10-CH3),10.5(13-CH2-CH3),9.2(4-CH3)。 13 CNMR (400MHz, DMSO) δ (ppm): 174.7 (1-CO), δ 165.7 (9-C=N-), 102.9 (1'-CH), 96.4 (3-O-CH), 83.7 ( 5-CH), 80.4 (3-CH), 78.1 (4″-CH), 77.3 (12-C), 77.0 (6-C), 76.8 (13-CH), 76.7 (5″-CH), 71.5 (2'-CH), 65.5 (3'-CH), 51.6 (9-NH-CH 2 CH 2 N), 48.0 (9-NH-CH 2 CH 2 N), 45.6 (9-NH-CH 2 CH 2 N( CH 2 CH 3 ) 2 ), 44.7 (2-CH), 40.3 (3′-N( CH 3 ) 2 ), 38.7 (7-CH 2 ), 35.2 (6″-CH), 32.6 (4-CH), 28.9 (4'-CH 2 ), 21.5 (6-CH 3 ), 21.1 (13 - CH 2 -CH 3 ), 18.6 (8-CH 3 ), 16.0 (12-CH 3 ) , 14.3 (10-CH 3 ), 10.5 (13- CH 2 -CH 3 ), 9.2 (4-CH 3 ).

效果实施例Effect Example

抗菌活性测试:Antibacterial activity test:

对上述合成的化合物1~19进行体外抗菌活性测试,将样品分别先用无水乙醇溶解,再用无菌水稀释成125μg/mL,然后依次对倍稀释。将20株G+和G-受试菌种分别接种在肉汤中,37℃培养过夜。用琼脂平板稀释法,用多点接种仪定量,接种每点105CFU。接种好菌种后,置于37℃培养箱内培养18h观察结果,得出化合物对受试菌的最低抑菌浓度(MIC值)。In vitro antibacterial activity test was carried out on the compounds 1-19 synthesized above. The samples were firstly dissolved in absolute ethanol, then diluted with sterile water to 125 μg/mL, and then double-diluted sequentially. Inoculate 20 strains of G + and G - test strains in the broth respectively, and culture overnight at 37°C. Use the agar plate dilution method, quantify with a multi-point inoculation instrument, and inoculate 10 5 CFU per point. After inoculating the strains, place them in an incubator at 37°C for 18 hours to observe the results, and obtain the minimum inhibitory concentration (MIC value) of the compound on the tested bacteria.

受试菌包括G+菌6株:金黄色葡萄球菌26003、表皮葡萄球菌26069、白色葡萄球菌26101、肺炎双球菌31002、肠球菌32220和丙型链球菌32206,G-菌14株:大肠杆菌44102、绿脓杆菌10124、肺炎杆菌46101、伤寒杆菌50097、产气杆菌45102、枸橼酸杆菌48017、普通变形杆菌49085、奇异变形杆菌49005、摩尔根变形杆菌49086、肠炎沙门氏菌50041、粘质沙雷氏菌41002、宋氏志贺氏菌51081、鲍氏志贺氏菌51313、福氏志贺氏菌51573。The tested bacteria included 6 strains of G + bacteria: Staphylococcus aureus 26003, Staphylococcus epidermidis 26069, Staphylococcus albus 26101, Diplococcus pneumoniae 31002, Enterococcus 32220 and Streptococcus C 32206, 14 strains of G - bacteria: Escherichia coli 44102 , Pseudomonas aeruginosa 10124, Bacillus pneumoniae 46101, Bacillus typhi 50097, Bacillus aerogenes 45102, Citrobacter 48017, Proteus vulgaris 49085, Proteus mirabilis 49005, Proteus morganensis 49086, Salmonella enteritidis 50041, Serratia marcescens Bacillus 41002, Shigella sonneri 51081, Shigella baumannii 51313, Shigella flexneri 51573.

测试结果见表3和表4。The test results are shown in Table 3 and Table 4.

表3table 3

表4Table 4

结论:合成的9-取代酰基腙克拉霉素衍生物(化合物1-10)对白色葡萄球菌、肺炎双球菌、肠球菌有很强的抗菌活性,化合物1和化合物9对金葡菌有较强抗菌活性,化合物1,2,3,4,5,6,8,9,10对丙型链球菌有较强抗菌活性。其中化合物1,4,9对金葡菌的抗菌活性优于阿奇霉素,化合物1-10对肠球菌的抗菌活性均优于阿奇霉素。Conclusion: The synthetic 9-substituted acylhydrazone clarithromycin derivatives (compound 1-10) have strong antibacterial activity against Staphylococcus albus, pneumococcus and enterococcus, and compound 1 and compound 9 have strong antibacterial activity against Staphylococcus aureus. Antibacterial activity, compounds 1, 2, 3, 4, 5, 6, 8, 9, and 10 have strong antibacterial activity against Streptococcus gamma. The antibacterial activities of compounds 1, 4 and 9 against Staphylococcus aureus are superior to azithromycin, and the antibacterial activities of compounds 1-10 against enterococcus are all superior to azithromycin.

合成的3-O-脱克拉定糖-3-氧代-9-取代酰基腙克拉霉素衍生物(化合物11-17)对金葡菌、白色葡萄球菌、肺炎双球菌、丙型链球菌有很强的抗菌活性,部分化合物(化合物11,12,16,17)对肠球菌有很强的抗菌活性。所有化合物对金葡菌的抗菌活性优于阿奇霉素(化合物11-17)。有4个化合物(化合物11,12,14,16)对丙型链球菌活性优于阿奇霉素;4个化合物(化合物11,12,16,17)对肠球菌的抗菌活性优于阿奇霉素。Synthetic 3-O-desclardinose-3-oxo-9-substituted acylhydrazone clarithromycin derivatives (compounds 11-17) are effective against Staphylococcus aureus, Staphylococcus albus, Diplococcus pneumoniae, Streptococcus gamma Strong antibacterial activity, some compounds (compounds 11, 12, 16, 17) have strong antibacterial activity against enterococci. All compounds had better antibacterial activity against S. aureus than azithromycin (compounds 11-17). There are 4 compounds (compounds 11, 12, 14, 16) which are more active than azithromycin against Streptococcus G; and 4 compounds (compounds 11, 12, 16, 17) which are more active against enterococci than azithromycin.

Claims (14)

1.一类如式I所示的大环内酯类化合物;1. A class of macrolide compounds as shown in formula I; 其中,R为C1~C3烷基,或H;Ra 3位的表示单键或双键,其为双键时,Rb不存在,其为单键时,Rb Wherein, R is C 1 ~C 3 alkyl, or H; R a is 3 digits Represents a single bond or a double bond. When it is a double bond, R b does not exist. When it is a single bond, R b is Rc为取代或未取代的C1~C3烷基、取代或未取代的C6~C10芳基、或者取代或未取代的C2~C4烯基;其中,取代的C6~C10芳基中的取代基为硝基或卤素,芳基中的取代基为邻位、对位或间位;取代的C1~C3烷基中的取代基为C6~C10芳基,或者C4~C8杂芳基,其中杂原子为N、O或S;取代的C2~C4烯基中的取代基为C6~C10芳基;R c is a substituted or unsubstituted C 1 -C 3 alkyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted C 2 -C 4 alkenyl group; wherein, the substituted C 6 -C 4 alkenyl group is The substituent in C 10 aryl is nitro or halogen, and the substituent in aryl is ortho, para or meta; the substituent in substituted C 1 ~C 3 alkyl is C 6 ~C 10 aryl or C 4 -C 8 heteroaryl, wherein the heteroatom is N, O or S; the substituent in the substituted C 2 -C 4 alkenyl is C 6 -C 10 aryl; X1和X2独立的为卤素;X 1 and X 2 are independently halogen; Rd和Re独立的为C1~C3烷基;R d and R e are independently C 1 -C 3 alkyl; n为1~3。n is 1-3. 2.如权利要求1所述的大环内酯类化合物,其特征在于:当Rc为取代或未取代的C1~C3烷基时,所述的C1~C3烷基为甲基、乙基或异丙基。2. The macrocyclic lactone compound according to claim 1, characterized in that: when R c is a substituted or unsubstituted C 1 -C 3 alkyl group, said C 1 -C 3 alkyl group is methyl radical, ethyl or isopropyl. 3.如权利要求1所述的大环内酯类化合物,其特征在于:Rc中,所述的取代的C6~C10芳基中的取代基为卤素时,所述的卤素为Cl。3. The macrocyclic lactone compound according to claim 1, characterized in that: in R c , when the substituent in the substituted C 6 -C 10 aryl is a halogen, the halogen is Cl . 4.如权利要求1所述的大环内酯类化合物,其特征在于:Rc中,取代的C1~C3烷基中的取代基为C4~C8杂芳基时,所述的C4~C8杂芳基为2-噻吩基或3-吲哚基。4. The macrocyclic lactone compound according to claim 1, characterized in that: in R c , when the substituent in the substituted C 1 -C 3 alkyl group is a C 4 -C 8 heteroaryl group, the The C 4 -C 8 heteroaryl group is 2-thienyl or 3-indolyl. 5.如权利要求1所述的大环内酯类化合物,其特征在于:当X1和X2独立的为卤素时,所述的卤素为氟、氯、溴或碘。5. The macrocyclic lactone compound according to claim 1 , characterized in that: when X1 and X2 are independently halogen, said halogen is fluorine, chlorine, bromine or iodine. 6.如权利要求1所述的大环内酯类化合物,其特征在于:所述的X1和X2的位置为2’位和5’位。6. macrolide compound as claimed in claim 1, is characterized in that: the position of described X1 and X2 is 2 ' position and 5 ' position. 7.如权利要求1所述的大环内酯类化合物,其特征在于:所述的X1和X2相同。7. macrolide compound as claimed in claim 1, is characterized in that: described X 1 and X 2 are identical. 8.如权利要求1所述的大环内酯类化合物,其特征在于:当Rd和Re独立的为C1~C3烷基时,所述的C1~C3烷基为乙基。8. The macrocyclic lactone compound according to claim 1, characterized in that: when R d and R e are independently C 1 -C 3 alkyl, said C 1 -C 3 alkyl is B base. 9.如权利要求1所述的大环内酯类化合物,其特征在于:所述的n为2。9. The macrolide compound as claimed in claim 1, characterized in that: said n is 2. 10.如权利要求1~9任一项所述的大环内酯类化合物,其特征在于:所述的化合物I为如下任一结构:10. The macrocyclic lactone compound according to any one of claims 1 to 9, characterized in that: said compound I is any one of the following structures: 其中,Ra和Rc的定义同权利要求1~9任一项中所述。Wherein, the definition of R a and R c is the same as that described in any one of claims 1-9. 11.如权利要求1~9任一项所述的大环内酯类化合物,其特征在于:所述的化合物I为如下任一化合物:11. The macrocyclic lactone compound according to any one of claims 1 to 9, characterized in that: said compound I is any one of the following compounds: Ia中,Rc为甲基、苯基、对硝基苯基、对氯苯基、苄基、苯乙基、苯乙烯基、噻吩-2-甲基、吲哚-3-甲基、吲哚-3-丙基;In Ia, R c is methyl, phenyl, p-nitrophenyl, p-chlorophenyl, benzyl, phenethyl, styryl, thiophene-2-methyl, indole-3-methyl, indole Indole-3-propyl; Ib中,Rc为苯基、对硝基苯基、对氯苯基、苄基、苯乙基、苯乙烯基或异丙基;In Ib, R c is phenyl, p-nitrophenyl, p-chlorophenyl, benzyl, phenethyl, styryl or isopropyl; Ic中,Ra In Ic, R a is 12.如权利要求1~9任一项所述的大环内酯类化合物的制备方法,其特征在于:其为下述方法中的任意一种:12. The preparation method of the macrolide compound as claimed in any one of claims 1 to 9, characterized in that: it is any one of the following methods: (一)当目标化合物I中,Ra时,R为C1~C3烷基时,将化合物II进行脱去羟基的酰基保护基的反应,即可;(1) When the target compound I, R a is When R is a C 1 -C 3 alkyl group, the compound II is subjected to the reaction of removing the acyl protecting group of the hydroxyl group; Rc1为Rc,各基团定义除特殊说明外均同权利要求1~9任一项所述;R c1 is R c , and the definitions of each group are the same as those described in any one of claims 1 to 9 unless otherwise specified; (二)当目标化合物I中,RaR为H或C1~C3烷基时,将化合物II’和RaX进行如下所示的亲核取代反应,即可;(2) When the target compound I, R a is When R is H or C 1 -C 3 alkyl, compound II' and R a X are subjected to the following nucleophilic substitution reaction; 其中,X为氯、溴或碘,各基团定义除特殊说明外均同权利要求1~9任一项所述。Wherein, X is chlorine, bromine or iodine, and the definition of each group is the same as that described in any one of claims 1-9 unless otherwise specified. 13.制备权利要求1~9任一项所述的化合物I的中间体化合物IIa、IIb或IIIb:13. Preparation of intermediate compound IIa, IIb or IIIb of compound I according to any one of claims 1 to 9: 其中,各基团的定义同权利要求1~9任一项所述。Wherein, the definition of each group is the same as that described in any one of claims 1-9. 14.如权利要求1~9任一项所述的化合物I在制备抗生素药物中的应用。14. Use of compound I according to any one of claims 1 to 9 in the preparation of antibiotic drugs.
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